Background: Immune checkpoint inhibitors (ICIs) were recently introduced into routine clinical practice, but the immunogenicity and safety of influenza vaccination in cancer patients receiving ICIs have not been elucidated. We explored immunogenicity and safety in cancer patients receiving ICIs compared to cancer patients receiving cytotoxic chemotherapy. Methods: Adult cancer patients receiving ICIs or cytotoxic agents were prospectively enrolled in a 1:2 ratio. They received an intramuscular seasonal quadrivalent influenza vaccine on day 1 of the chemotherapeutic cycle. The serum hemagglutination inhibition (HAI) antibody titers were examined before and 4 weeks after vaccination. The primary endpoint was seroprotection rate and secondary endpoints were seroconversion rate and geometric mean antibody titer. Immune-related adverse events (irAEs) were screened by pre-defined measures. Findings: Among 154 eligible patients, 46 and 90 patients in the ICI and cytotoxic chemotherapy groups, respectively, were finally examined for HAI antibody titers. Seroprotection rates were higher in the ICI group than in the cytotoxic chemotherapy group (H1N1, 76% vs. 68%, P=0.111; H3N2, 89% vs. 70%, P=0.005; B-Yamagata, 83% vs. 54%, P=0.002; B-Victoria, 85% vs. 48%, P<0.001) and seroconversion rates were also higher in the ICI group (H1N1, 57% vs. 39%, P=0.086; H3N2, 52% vs. 27%, P=0.006; B-Yamagata, 54% vs. 30%, P=0.007; B-Victoria, 65% vs. 28%, P<0.001). The frequency of vaccine-related adverse events was comparable between the two groups. Only 4 (8.5%) irAEs occurred during the study period, which were all grade 1. Interpretation: Cancer patients receiving ICIs reach higher levels of influenza immunity by vaccination than those receiving cytotoxic chemotherapy, without increased frequency or severity of irAEs. Annual influenza vaccination should be encouraged in cancer patients receiving ICIs. Trial Registration Number: The study was registered at ClinicalTrials.gov (identifier NCT03590808). Funding Statement: GC Pharma (Yongin, Republic of Korea) and Seoul National University Hospital Research Fund (Seoul, Republic of Korea; No.04-2018-0520). Declaration of Interests: BK reports grants and personal fees from AstraZeneca, grants and personal fees from MSD, grants from ONO Pharmaceutical, personal fees from Genexine, outside the submitted work. S-AI reports grants and personal fees from AstraZeneca, grants and personal fees from Pfizer, personal fees from Amgen, personal fees from Eisai, personal fees from Hanmi Corp., personal fees from Novartis, personal fees from Roche, outside the submitted work. WBP reports grants from GC Pharma, grants from Seoul National University Hospital Research Fund, during the conduct of the study. All other authors declare no competing interests. Seoul National University Hospital reports grants from Alpha Biopharma, grants from AstraZeneca/MedImmune, grants from Hanmi Corp., grants from Janssen, grants from Merus, grants from Mirati Therapeutics, grants from MSD, grants from Novartis, grants from ONO Pharmaceutical, grants from Pfizer, grants from Roche/Genentech, grants from Takeda, grants from TP Therapeutics, grants from Xcovery, grants from Yuhan, outside the submitted work. Ethics Approval Statement: Written informed consents were obtained from all participants prior to vaccination. The study was approved by the Institutional Review Board of Seoul National University Hospital (IRB approval No. H-1806-088-951) and Seoul National University Bundang Hospital (IRB approval No. B-1808/484- 402).