First-line renin-angiotensin system (RAS) inhibitors are recommended for diabetic patients because of their potential nephron-protective properties. For hypertensive patients with type 2 diabetes mellitus, little is known about first-line RAS inhibitors vs. other first-line antihypertensive agents in terms of cardiovascular outcomes. We performed a meta-analysis of randomized controlled trials (RCTs) to assess the comparative efficacy of first-line RAS inhibitors vs. other first-line antihypertensive drug classes in hypertensive patients with type 2 diabetes mellitus. We identified RCTs by searching the Cochrane Central Register of Controlled Trials, MEDLINE and EMBASE up to December 15, 2015. Eighteen RCTs involving 18,862 participants were included. First-line RAS inhibitors were not different from first-line diuretics for all the primary outcomes. First-line RAS inhibitors reduced major cardiovascular events (2 RCTs, relative risk [RR] 0.78, 95% confidence interval [CI] 0.66, 0.91) and heart failure (4 RCTs, RR 0.72, 95% CI 0.61, 0.83) compared to first-line calcium channel blockers. Compared to β-blockers, RAS inhibitors reduced the risk of all-cause mortality (1 RCT, RR 0.63, 95% CI 0.47, 0.84), major cardiovascular events (1 RCT, RR 0.76, 95% CI 0.62, 0.93) and heart failure (1 RCT, RR 0.60, 95% CI 0.40, 0.92). Our meta-analysis indicates that, in patients with type 2 diabetes mellitus and hypertension, first-line RAS inhibitors reduced adverse cardiovascular events to the same degree as first-line diuretics but to a greater degree than first-line calcium channel blockers and first-line beta blockers.