['Previous observational studies reported that concomitant use of clopidogrel and proton pump inhibitors (PPIs) in patients with prior acute coronary syndrome (ACS) was associated with adverse cardiovascular outcomes. We investigated whether H(2)-receptor antagonist (H(2)RA) is an alternative to PPI in patients with ACS.', 'We conducted a population-based retrospective cohort study of 6552 patients in Taiwan discharged for ACS between 2002 and 2005. Patients were divided into 5 cohorts: clopidogrel plus H(2)RA (n = 252), clopidogrel plus PPI (n = 311), clopidogrel alone (n = 5551), H(2)RA alone (n = 235), and PPI alone (n = 203). The primary outcome was rehospitalization for ACS or all-cause mortality within 3 month of rehospitalization.', 'The 1-year cumulative incidence of the primary outcome was 26.8% (95% CI: 21.5%-33.0%) in the clopidogrel plus H(2)RA cohort and 33.2% (95% CI: 27.8%-39.4%) in the clopidogrel plus PPI cohort, compared with 11.6% (95% CI: 10.8%-12.5%) in the clopidogrel alone cohort (P < .0001). No significant difference was observed between the PPI alone cohort (11.0%; 95% CI: 7.1%-16.8%), the H(2)RA alone cohort (11.8%; 95% CI: 8.2%-16.8%), and the clopidogrel alone cohort in terms of the primary outcome. The number needed to harm was 7 with concomitant H(2)RA and 5 with concomitant PPI. On multivariate analysis, concomitant H(2)RA and PPI were independent risk factors predicting adverse outcomes (adjusted hazard ratios, 2.48 and 3.20, respectively; P < .0001).'] Are histamine2-receptor antagonists an alternative to proton pump inhibitor in patients receiving clopidogrel?