Objectives The study investigated whether the number of participants enrolled per site in an acute heart failure trial is associated with participant characteristics and outcomes. Background Whether and how site enrollment volume affects clinical trials is not known. Methods A total of 4,133 participants enrolled among 359 sites were grouped on the basis of total enrollment into 1 to 10, 11 to 30, and >30 participants per site and were compared for outcomes (cardiovascular mortality or heart failure hospitalization). Results Per-site enrollment ranged from 0 to 75 (median 6; 77 sites had no enrollment). Regional differences in enrollment were noted between North and South America, and Western and Eastern Europe (p < 0.001). Participants from sites with fewer enrollments were more likely to be older and male, have lower ejection fraction and blood pressure as well as worse comorbidity and laboratory profile, and were less likely to be on angiotensin-converting enzyme inhibitors or aldosterone antagonists. During a median follow-up of 9.9 months, 1,700 (41%) participants had an outcome event. Compared to event rate at sites with >30 participants (32%), those with 1 to 10 (51%, hazard ratio [HR]: 1.77, 95% confidence interval [CI]: 1.56 to 2.02) and 11 to 30 (42%, HR: 1.44, 95% CI: 1.28 to 1.62) participants per site groups had worse outcomes. This relationship was comparable across regions (p = 0.43). After adjustment for risk factors, participants enrolled at sites with fewer enrollees were at higher risk for adverse outcomes (HR: 1.26, 95% CI: 1.08 to 1.46 for 1 to 10; HR: 1.22, 95% CI: 1.07 to 1.38 for 11 to 30 vs. >30 participant sites). Higher proportion of participants from site with >30 participants completed the protocol (45.5% for <10, 61.7% for 11 to 30, and 68.4% for sites enrolling >30 participants; p < 0.001). Conclusions Baseline characteristics, protocol completion, and outcomes differed significantly among higher versus lower enrolling sites. These data imply that the number of participant enrolled per site may influence trials beyond logistics.