Background: Repeat hospitalizations of patients with atherosclerosis represent a considerable burden on the health care system. We sought to determine whether clopidogrel compared with aspirin decreases the need for rehospitalization for ischemia and bleeding. Methods and Results: The Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial was a randomized, blinded, multicenter, trial of 19,185 patients with atherosclerotic disease manifested as recent ischemic stroke or myocardial infarction or symptomatic peripheral arterial disease. Without any double- counting of events, the number of rehospitalizations for ischemic events (defined as angina, transient ischemic attack, or limb ischemia) or bleeding events was determined for the entire cohort. There was a significant reduction in the total number of rehospitalizations for ischemic events or bleeding with clopidogrel use compared with aspirin (1502 vs 1673; P = .010) over an average of 1.6 years of treatment. This reduction in rehospitalization was consistent across individual outcomes of angina, transient ischemic attack, limb ischemia, and bleeding. Compared with aspirin, clopidogrel also resulted in a 7.9% relative risk reduction in a combined end point of vascular death, stroke, myocardial infarction; or rehospitalization for ischemic events or bleeding (15.1% to 13.7% at 1 year; P = .011). Adjusting for baseline prognostic variables, clopidogrel therapy was an independent predictor for reduction of vascular death, stroke, myocardial infarction, or rehospitalization for ischemic events or bleeding (P = .009). Conclusions: Treatment with clopidogrel results in a significant decrease in the need for rehospitalization for ischemic events or bleeding compared with aspirin. This meaningful end point tracks well with other, more traditional measures of outcome and has incremental value beyond such end points.