AbstractImmune checkpoint inhibitors (ICIs) combined with the anti‐angiogenesis drug bevacizumab is one of the future directions of immunotherapy. However, the potential adverse drug reactions (ADRs) caused by combination therapy remain unclear. Current research on ADRs of combination therapy in cancer patients is extremely limited. Our study aims to help determine the safety of combination therapy. We downloaded the ADR reports on combination therapy, from the first quarter of 2012 to the fourth quarter of 2021, from the FDA adverse event reporting system (FAERS) database and conducted a large‐scale retrospective study. The ADR signals were monitored by reporting odds ratio (ROR) and analyzing the risk of different ADRs in patients with Pan‐cancer. A total of 2094 cases were selected, after excluding duplicate data and the use of chemotherapy drugs. We evaluated the risk of ADR in Pan‐cancer patients. Combination therapy was an independent risk factor for adverse drug reactions associated with interstitial lung disease (OR: 8.62; 95% CI: 6.14‐12.10, P < .0001), hypertension (OR: 1.35; 95% CI: 1.11‐1.65, P < .01) and gastrointestinal bleeding (OR: 3.16; 95% CI: 2.21‐4.51, P < .0001). A subgroup analysis revealed that the risk of endocrine system‐related ADRs was elevated in patients receiving different combination therapies or with certain tumor types. We retrospectively studied the ADR of combination therapy in Pan‐cancer patients and analyzed the distribution characteristics of ADR from the perspectives of treatment strategy and cancer types to provide recommendations for the individualized management of patients receiving combination therapy.