IMPORTANCE: Hypercholesterolemia is widely undertreated. OBJECTIVE: To project anticipated improvements in treatment and outcomes under full implementation of US and European pharmacologic treatment recommendations. DESIGN, SETTING, AND PARTICIPANTS: The study sample included a total of 4980 adults aged 40-75 years from the 2013 through March 2020 US National Health and Nutrition Examination Survey (NHANES). We estimated the number of individuals eligible to receive versus currently receiving lipid lowering therapy (LLT) after applying: (1) the AHA/ACC guideline ("2018 US guideline"); (2) the ESC/EAS guideline ("2019 EU guideline"); and (3) the ACC expert decision pathway ("2022 US pathway"). MAIN OUTCOMES AND MEASURES: (1) Number of individuals eligible for LLT; and (2) expected reduction in LDL-C and major cardiovascular events. RESULTS: The study sample represented 131 million US adults. A total of 23% of the NHANES primary prevention cohort was currently using LLT compared to the 2018 US guideline/2022 US pathway (47% eligible) and the 2019 EU guideline (87% eligible). LLT use was significantly lower than the proportion of eligible patients for all therapies, including statins (66% use vs. 100% eligibility), ezetimibe (4% vs. 31-74% eligibility under the various recommendations) and proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) (0% vs. 11-53% eligibility). The additional overall median LDL-C reduction expected under fully guideline concordant care was 37.2 (IQR 6.7-57.6) mg/dL, 48.5 (IQR 33.0-69.9) mg/dL, and 46.8 (IQR 7.2-67.6) mg/dL based on the 2018 US guideline, 2019 EU guideline and the 2022 US pathway, respectively. These reductions in LDL-C could yield a 21-27% relative reduction in risk of major cardiovascular events. CONCLUSIONS AND RELEVANCE: Aligning treatment of hypercholesterolemia with US and European guidelines would generate major clinical and public health gains.