AIM: To evaluate and analyze the post-marketing adverse drug reaction (ADR) signals of polatuzumab vedotin, so as to provide reference for clinical safety management. METHODS: Using the FDA adverse drug event reporting system (FAERS) database and OpenVigil data platform, the ADR reports of polatuzumab vedotin were collected from June 10, 2019 (FDA approval for marketing) to the March 31, 2023. The ADR signals were detected by using the reporting odds ratio (ROR) and proportional reporting ratio (PRR) in the proportional imbalance method. To increase the threshold and obtain stronger and more frequently occurring ADRs, a second screening of signals was performed. RESULTS: A total of 2 408 ADR reports related to polatuzumab vedotin were collected, and 83 ADR signals were detected after secondary screening. 26 ADR signals were not mentioned in the drug instructions such as abnormal spinal magnetic resonance imaging, increased bone resorption, osteolysis, decreased aspartate aminotransferase, decreased alanine aminotransferase, hypofibrinogenemia, and pulmonary embolism. The system organ classes with a high signal counts or cumulative number of cases included infections and invasive diseases (24 signals, 632 cases), various examinations (17 signals, 675 cases), blood and lymphatic system diseases (11 signals, 734 cases), various nervous system diseases (7 signals, 153 cases), immune system diseases (3 signals, 95 cases), systemic diseases and various reactions at the site of administration (2 signals, 145 cases), and systemic diseases and various reactions at the site of administration (2 signals, 87 cases), etc. CONCLUSION: In addition to the common ADRs suggested by the instructions, this study identified new ADR risk signals for polatuzumab vedotin. In the clinical application of polatuzumab vedotin, in addition to the ADR mentioned in the instructions such as infections, myelosuppression, peripheral neuropathies, infusion-related reactions, and abnormal liver function, attention should also be paid to the risk signals not mentioned such as abnormal spinal magnetic resonance imaging, and increased bone resorption.