Background: IrAEs have been described with ICB, though the overall risk of irAEs with these drugs remains unclear. Our aim was to determine the incidence and the relative risk (RR) of key irAEs from approved immune checkpoint blockers (ICB) to better characterize their safety profile. Methods: PubMed and Medline databases were searched from Jan1996 to Oct2015. Eligible studies included randomized phase II/III trials with non-ICB control arms. Statistical analyses were conducted to calculate the summary incidence, RRs, and 95% CIs, using random-effects models. The 5 selected key irAEs included: colitis, transaminitis (increased AST), immune-related rash, hypothyroidism, and pneumonitis. Results: A total of 6133 patients (pts) from 12 trials were included: 3499 pts assigned to single-agent ICB arms (nivolumab [n = 1298], pembrolizumab [n = 357], ipilimumab [n = 1844]) and 2634 to non-ICB arms. All-grade incidence of each selected key irAE with ICB was: colitis 3.1%, increased AST 7.8%, rash 16.7%, hypothyroidism 4.2 % and pneumonitis 2.4%. Compared to non-ICB arms, the RR of all-grade irAE with ICB was: colitis 8.88 (95% CI, 5.09 to 15.5; P < 0.001), increased AST 1.89 (95% CI, 1.05 to 3.40; P = 0.034), rash 2.36 (95% CI, 1.39 to 3.99; P < 0.001), hypothyroidism 7.17 (95% CI, 3.57 to 14.4; P < 0.001) and pneumonitis 3.96 (95% CI, 0.68 to 23.2; P = 0.127). Grade 3/4 incidence of each selected key irAE with ICB was: colitis 2.0%, increased AST 2.0%, rash 1.0%, hypothyroidism 0.3% and pneumonitis 0.9%. Compared to non-ICB arms, the RR of grade 3/4 irAE with ICB was: colitis 6.83 (95% CI 2.68 to 17.4; P < 0.001) and increase AST 3.35 (95% CI 1.25 to 8.98; P = 0.016). Ipilimumab had higher RR of grade 3/4 colitis (p = 0.033) and all-grade rash (p = 0.047), than nivolumab/pembrolizumab, but no other significant differences were found. Conclusions: This meta-analysis offers substantial evidence that ICB treatment is associated with a small but significant increase in the risk of several all-grade irAEs analyzed, as well as grade 3/4 colitis and transaminitis compared to non-ICB treated pts.