Experimental considerations suggest both potential harm and benefit from statin therapy in patients with severe heart failure. However, relations of statin therapy with clinical outcomes in severe heart failure are not well established. Using data from the Prospective Randomized Amlodipine Survival Evaluation (PRAISE) trial, we evaluated associations of statin therapy with total mortality among 1,153 patients with severe heart failure (ejection fraction <30% and New York Heart Association class IIIB or IV symptoms) of ischemic and nonischemic etiologies. Statin therapy was administered to 134 patients (12%) during the study period. Over a 1.3-year mean follow-up, there were 413 deaths (29 deaths/100 person-years). Adjusting for age, gender, diabetes, smoking, heart failure etiology, ejection fraction, and New York Heart Association class, statin therapy was associated with a 62% lower risk of death (hazard ratio 0.38, 95% confidence interval 0.23 to 0.65), or 1 fewer death/5 patients taking statin therapy for 1 year. This association was not greatly altered by additional adjustment for a variety of other patient characteristics, including serum cholesterol levels. After propensity score analyses, statin therapy was still associated with a 48% lower risk of death (hazard ratio 0.52, 95% confidence interval 0.30 to 0.89). Although this observational study does not prove causality, further investigation of potential benefits of statins in patients with severe heart failure appears warranted.