Abstract Immune-mediated thrombotic thrombocytopenic purpura (iTTP) survivors experience high rates of adverse health sequelae and increased mortality over long-term follow-up. We conducted this multicenter cohort study to evaluate long-term mortality and causes of death in iTTP survivors. Between 2003 and 2020, 222 patients were enrolled in the Ohio State University and Johns Hopkins TTP registries and followed for a median of 4.5 (interquartile range [IQR], 75 0.4-11.5) years. Nine patients died during their first iTTP episode, and 29 patients died during follow-up. Mortality rate was 1.8 times higher than expected from an age-, sex-, and race-adjusted reference population. Cardiovascular disease was a leading primary cause of death (27.6%) tied with relapsed iTTP (27.6%), followed by malignancy (20.7%), infection (13.8%), and other causes (10.3%). Male sex (hazard ratio [HR], 3.74; 95% confidence interval [CI], 1.65-8.48), increasing age (HR, 1.04; 95% CI, 1.01-1.07), and number of iTTP episodes (HR, 1.10; 95% CI, 1.01-1.20) were associated with mortality in a model adjusted for African American race (HR, 0.70; 95% CI, 0.30-1.65), hypertension (HR, 0.47; 95% CI, 0.20-1.08), chronic kidney disease (HR 1.46; 95% CI, 0.65-3.30), and site (HR, 1.46; 95% CI, 0.64–3.30). There was a trend toward shorter survival in patients with lower ADAMTS13 activity during remission (P = .078). Our study highlights the need for survivorship care and investigation focused on cardiovascular disease and early mortality in TTP survivors.