We systematically reviewed randomized controlled trials (RCTs) assessing the effectiveness of computerized decision support systems (CDSSs) featuring rule- or algorithm-based software integrated with electronic health records (EHRs) and evidence-based knowledge. We searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and Cochrane Database of Abstracts of Reviews of Effects. Information on system design, capabilities, acquisition, implementation context, and effects on mortality, morbidity, and economic outcomes were extracted. Twenty-eight RCTs were included. CDSS use did not affect mortality (16 trials, 37395 patients; 2282 deaths; risk ratio [RR] = 0.96; 95% confidence interval [CI] = 0.85, 1.08; I(2) = 41%). A statistically significant effect was evident in the prevention of morbidity, any disease (9 RCTs; 13868 patients; RR = 0.82; 95% CI = 0.68, 0.99; I(2) = 64%), but selective outcome reporting or publication bias cannot be excluded. We observed differences for costs and health service utilization, although these were often small in magnitude. Across clinical settings, new generation CDSSs integrated with EHRs do not affect mortality and might moderately improve morbidity outcomes.