Treatment with ibuprofen might limit the cardioprotective effects of aspirin. We aimed to assess whether patients with known cardiovascular disease who take low-dose aspirin and ibuprofen have increased risk of cardiovascular mortality. We studied 7107 patients who were discharged after first admission for cardiovascular disease between April, 1989, and April, 1997, and who were prescribed low-dose aspirin (<325 mg/day) and survived for at least 1 month. Compared with those who used aspirin alone, patients taking aspirin plus ibuprofen had an increased risk of all-cause mortality (adjusted hazard ratio 1·93, 95% CI 1·30–2·87, p=0·0011) and cardiovascular mortality (1·73, 1·05–2·84, p=0·0305). Our finding lends support to the hypothesis that ibuprofen may interact with the cardioprotective effects of aspirin, at least in patients with established cardiovascular disease.