This report provides a final summary of the principal findings and key conclusions of a study supported by an HEI grant aimed at "Assessing Adverse Health Effects of Long-Term Exposure to Low Levels of Ambient Air Pollution." It is the second and final report on this topic. The study was designed to advance four critical areas of inquiry and methods development. First, it focused on predicting short- and long-term exposures to ambient fine particulate matter (PM), nitrogen dioxide (NO), and ozone (O) at high spatial resolution (1 km × 1 km) for the continental United States over the period 2000-2016 and linking these predictions to health data. Second, it developed new causal inference methods for estimating exposure-response (ER) curves (ERCs) and adjusting for measured confounders. Third, it applied these methods to claims data from Medicare and Medicaid beneficiaries to estimate health effects associated with short- and long-term exposure to low levels of ambient air pollution. Finally, it developed pipelines for reproducible research, including approaches for data sharing, record linkage, and statistical software. Our HEI-funded work has supported an extensive portfolio of analyses and the development of statistical methods that can be used to robustly understand the health effects of short- and long-term exposure to low levels of ambient air pollution. Our Phase 1 report (Dominici et al. 2019) provided a high-level overview of our statistical methods, data analysis, and key findings, grouped into the following five areas: (1) exposure prediction, (2) epidemiological studies of ambient exposures to air pollution at low levels, (3) sensitivity analysis, (4) methodological contributions in causal inference, and (5) an open access research data platform. The current, final report includes a comprehensive overview of the entire research project. Considering our (1) massive study population, (2) numerous sensitivity analyses, and (3) transparent assessment of covariate balance indicating the quality of causal inference for simulating randomized experiments, we conclude that conditionally on the required assumptions for causal inference, our results collectively indicate that long-term PM exposure is likely to be causally related to mortality. This conclusion assumes that the causal inference assumptions hold and, more specifically, that we accounted adequately for confounding bias. We explored various modeling approaches, conducted extensive sensitivity analyses, and found that our results were robust across approaches and models. This work relied on publicly available data, and we have provided code that allows for reproducibility of our analyses. Our work provides comprehensive evidence of associations between exposures to PM NO, and O and various health outcomes. In the current report, we report more specific results on the causal link between long-term exposure to PM and mortality, even at PM levels below or equal to 12 μg/m, and mortality among Medicare beneficiaries (ages 65 and older). This work relies on newly developed causal inference methods for continuous exposure. For the period 2000-2016, we found that all statistical approaches led to consistent results: a 10-μg/m decrease in PM led to a statistically significant decrease in mortality rate ranging between 6% and 7% (= 1 - 1/hazard ratio [HR]) (HR estimates 1.06 [95% CI, 1.05 to 1.08] to 1.08 [95% CI, 1.07 to 1.09]). The estimated HRs were larger when studying the cohort of Medicare beneficiaries that were always exposed to PM levels lower than 12 μg/m (1.23 [95% CI, 1.18 to 1.28] to 1.37 [95% CI, 1.34 to 1.40]). Comparing the results from multiple and single pollutant models, we found that adjusting for the other two pollutants slightly attenuated the causal effects of PM and slightly elevated the causal effects of NO exposure on all-cause mortality. The results for O remained almost unchanged. We found evidence of a harmful causal relationship between mortality and long-term PM exposures adjusted for NO and O across the range of annual averages between 2.77 and 17.16 μg/m (included >98% of observations) in the entire cohort of Medicare beneficiaries across the continental United States from 2000 to 2016. Our results are consistent with recent epidemiological studies reporting a strong association between long-term exposure to PM and adverse health outcomes at low exposure levels. Importantly, the curve was almost linear at exposure levels lower than the current national standards, indicating aggravated harmful effects at exposure levels even below these standards. There is, in general, a harmful causal impact of long-term NO exposures to mortality adjusted for PM and O across the range of annual averages between 3.4 and 80 ppb (included >98% of observations). Yet within low levels (annual mean ≤53 ppb) below the current national standards, the causal impacts of NO exposures on all-cause mortality are nonlinear with statistical uncertainty. The ERCs of long-term O exposures on all-cause mortality adjusted for PM and NO are almost flat below 45 ppb, which shows no statistically significant effect. Yet we observed an increased hazard when the O exposures were higher than 45 ppb, and the HR was approximately 1.10 when comparing Medicare beneficiaries with annual mean O exposures of 50 ppb versus those with 30 ppb. institutions, including those that support the Health Effects Institute; therefore, it may not reflect the views or policies of these parties, and no endorsement by them should be inferred. A list of abbreviations and other terms appears at the end of this volume.