Available evidence shows that the incidence of toxicities associated with cancer immunotherapy, such as programmed cell death 1 (PD-1) and programmed cell death 1 ligand 1 (PD-L1)-related toxicities, is estimated to be between 0.3% and 1.3%.This systematic review aimed to investigate cancer patients' susceptibility to toxicities associated with PD-1/PD-L1 inhibitors, and establish a clinically relevant landscape of side effects of PD-1/PD-L1 inhibitors.Relevant publications from PubMed, Embase, Cochrane Library, Web of Science and China National Knowledge Infrastructure (CNKI) between 2014 to 2019.We searched randomized controlled trials (RCTs) reporting treatment-related toxicities associated with PD-1 and PD-L1 inhibitors in treatment of cancers. The primary endpoint was to assess the difference in the incidences of toxicities between cancer patients who did and did not receive PD-1/PD-L1 inhibitors. A total of 29 RCTs, incorporating 8,576 patients, met the eligibility criteria.We calculated the pooled relative risks (RRs) and corresponding 95% confidence intervals (95% CIs) using a random-effects model and assessed the heterogeneity between different groups. The subgroup analyses were conducted based on cancer type, toxicity grade (severity), system and organ, treatment regimens in the intervention arm and control arm, PD-1/PD-L1 inhibitor drug type, and cancer type.A total of 11 categories (e.g., endocrine toxicity), 39 toxicity types (e.g., hyperthyroidism) were identified. For toxicities at any grade, those treated with PD-1/PD-L1 inhibitors were at lower risks for gastrointestinal toxicity, hematologic toxicity, and treatment event leading to discontinuation; and were at higher risks for respiratory toxicity (all P<0.05). Those treated with PD-1/PD-L1 inhibitors were at lower risks for fatigue, asthenia, peripheral edema, and were at higher risks for pyrexia, cough, dyspnea, pneumonitis, pruritus.The present research is a meta-analysis at the study level rather than at the patient level, insights on risk factors associated with the development of toxicities cannot be found in our study. There was a possible overlap in Common Terminology Criteria for Adverse Events (CTCAE) definitions which prevents understanding the true rates of specific toxicities.For most toxicity types based on system and organ, the incidence proportions for patients in the intervention arm were lower than those in the control arm, which suggested the general safety of PD-1/PD-L1 inhibitors against conventional chemotherapy and cytotoxic t-lymphocyte-associated protein 4 (CTLA-4) inhibitors. Future research should focus on taking effective targeted measures to decrease the risks of different toxicities for different patient populations.We registered the research protocol with PROSPERO (registration number CRD42019135113).Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.