Nivolumab, an immune checkpoint inhibitor, has revolutionized the treatment of many cancers. Due to its novel mechanisms of action, nivolumab induces a distinct profile of adverse events. Currently, the incidence and risk of developing serious adverse events (SAEs) or fatal adverse events (FAEs) following nivolumab administration are unclear. We conducted a systematic search for phase 2 and phase 3 nivolumab trials in PubMed and Embase from inception to June 2018. Data on SAEs/FAEs were extracted from each study and pooled to calculate the overall incidence and odds ratios (ORs). A total of 21 trials with 6173 cancer patients were included in this study. The overall incidence of SAEs and FAEs with nivolumab were 11.2% (95% CI, 8.7-13.8%) and 0.3% (95% CI, 0.1-0.5%), respectively. The incidence of SAEs varied significantly with cancer type and clinical phase, but no evidence of heterogeneity was found for FAEs. Compared with conventional treatment, the administration of nivolumab did not increase the risk of SAEs (OR, 0.69; 95% CI, 0.34-1.40; p = 0.29) or FAEs (OR, 0.61; 95% CI, 0.27-1.39; p = 0.24). SAEs occurred in the major organ systems in a dispersed manner, with the most common toxicities appearing in the respiratory (21.4%), gastrointestinal (7.7%), and hepatic systems (6.6%). The most common cause of SAEs/FAEs was pneumonitis. Although nivolumab is a relatively safe antitumor agent, nononcologists should be advised of the potential adverse events. Additionally, future studies are needed to identify patients at high risk of SAEs/FAEs to aid in the development of optimal monitoring strategies and the exploration of treatments to decrease the risks.