BACKGROUND: Sepsis is a frequent reason for ICU admission and a leading cause of death. Its incidence has been increasing over the past decades. While hospital mortality is decreasing, it is recognized that the sequelae of sepsis extend well beyond hospitalization and are associated with a high mortality rate that persists years after hospitalization. The aim of this study was to disentangle the relative contribution of sepsis (infection with multi-organ failure), of infection and of inflammation, as reasons for ICU admission to long-term survival. This was done as infection and inflammation are both cardinal features of sepsis. We assessed the 3-year mortality of ICU patients admitted with sepsis, with individually matched ICU patients with an infection but not sepsis, and with an inflammatory illness not caused by infection, discharged alive from hospital. METHODS: A multicenter cohort study of adult ICU survivors admitted between January 1st 2007 and January 1st 2019, with sepsis, an infection or an inflammatory illness. Patients were classified within the first 24 h of ICU admission according to APACHE IV admission diagnoses. Dutch ICUs (n = 78) prospectively recorded demographic and clinical data of all admissions in the NICE registry. These data were linked to a health care insurance claims database to obtain 3-year mortality data. To better understand and distinct the sepsis cohort from the non-sepsis infection and inflammatory condition cohorts, we performed several sensitivity analyses with varying definitions of the infection and inflammatory illness cohort. RESULTS: Three-year mortality after discharge was 32.7% in the sepsis (N = 10,000), 33.6% in the infectious (N = 10,000), and 23.8% in the inflammatory illness cohort (N = 9997). Compared with sepsis patients, the adjusted HR for death within 3 years after hospital discharge was 1.00 (95% CI 0.95-1.05) for patients with an infection and 0.88 (95% CI 0.83-0.94) for patients with an inflammatory illness. CONCLUSIONS: Both sepsis and non-sepsis infection patients had a significantly increased hazard rate of death in the 3 years after hospital discharge compared with patients with an inflammatory illness. Among sepsis and infection patients, one third died in the next 3 years, approximately 10% more than patients with an inflammatory illness. The fact that we did not find a difference between patients with sepsis or an infection suggests that the necessity for an ICU admission with an infection increases the risk of long-term mortality. This result emphasizes the need for greater attention to the post-ICU management of sepsis, infection, and severe inflammatory illness survivors.