BACKGROUND Aspirin is the prophylactic antiplatelet drug of choice for people with cardiovascular disease. However, protection with antiplatelet therapy in people with a high risk of cardiovascular disease is unsatisfactory in absolute terms. Adding a second antiplatelet drug to aspirin may produce additional benefit for those at high risk and those with established cardiovascular disease. OBJECTIVE To quantify the effects (both benefit and harm) of adding clopidogrel to standard long-term aspirin therapy for preventing cardiovascular events in people at high risk of cardiovascular disease and those with established cardiovascular disease. METHODS CENTRAL (Issue 2 2006), MEDLINE (2002 to May 2006) and EMBASE (2002 to May 2006) were searched. Online registers of ongoing trials and reference lists from original articles and reviews were checked. METHODS All randomized controlled trials comparing long term (>30 days) use of aspirin plus clopidogrel with aspirin plus placebo or aspirin alone in patients with coronary disease, ischemic cerebrovascular disease, peripheral arterial disease, or at high risk of atherothrombotic disease (with data for at least one of the outcomes) were included. METHODS Data were collected on the following outcomes and analysed where appropriate: mortality (from myocardial infarction, stroke, cardiovascular causes, all-causes), non-fatal myocardial infarction, non-fatal stroke, unstable angina, heart failure, revascularizations, major and minor bleeding, and all adverse events. Quantitative analysis of outcome was based on an intention-to-treat principle. The overall treatment effect was estimated by the pooled odds ratio (OR) with 95% confidence interval (CI) using a fixed-effect model (Mantel-Haenszel). RESULTS Two RCTs were found. Patients enrolled in the CHARISMA study were at high risk for cardiovascular events, either with or without an established cardiovascular disease. Patients enrolled in the CURE study had a recent non-ST segment elevation acute coronary syndrome. The use of clopidogrel plus aspirin, compared with placebo plus aspirin, was associated with a lower risk of cardiovascular events (OR: 0.87, 95% CI 0.81 to 0.94; P<0.01) and a higher risk of major bleeding (OR 1.34, 95% CI 1.14 to 1.57; P<0.01). Overall, we would expect 13 cardiovascular events to be prevented for every 1000 patients treated with the combination, but 6 major bleeds would be caused. Treatment effects differed in the two trials: the CURE trial, confined to people with acute non-ST segment coronary syndromes, showed definite evidence of benefit from treatment. For every 1000 people treated for an average of 9 months, 23 events would be avoided and 10 major bleeds would be caused. In the CHARISMA trial that randomized people at high cardiovascular risk defined either in terms of pre-existing cardiovascular diseases or risk factors, the effects of treatment were less marked and were consistent with the play of chance. For every 1000 people treated for an average of 28 months, 5 cardiovascular events would be avoided and 3 major bleeds would be caused. CONCLUSIONS The available evidence demonstrates that the use of clopidogrel plus aspirin is associated with a reduction in the risk of cardiovascular events compared with aspirin alone in patients with acute non-ST coronary syndrome. In patients at high risk of cardiovascular disease but not presenting acutely, there is only weak evidence of benefit and hazards of treatment almost match any benefit obtained.