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Background We previously reported that mRNA vaccines sensitize tumors to immune checkpoint inhibitors (ICIs) in preclinical models and small retrospective cohorts of patients with lung cancer and melanoma. Here, we tested this effect in a large, multi-histology patient cohort.Methods We utilized institutional databases to identify patients treated with immune checkpoint inhibitors (ICIs) from 11/1/2018 to 5/5/2023. We extracted clinical data and SARS-COV-2 vaccination dates (if applicable) for each patient. Overall survival (OS) was defined from the initiation of a patient’s first ICI to the date of most recent follow-up/death. We defined the ‘pandemic era’ beginning 12/11/2020, the date of the first SARS-CoV-2 mRNA vaccine approval. Comparisons utilized log-rank tests and Cox Proportional Hazards Regression.Results We identified 12,523 ICI-treated patients from 11/2018 to 5/2023, including 1,762 who received a SARS-COV-2 mRNA vaccine within 100 days of initiating ICI and 10,761 who did not. Baseline characteristics were similar between groups. Patients treated since the start of the pandemic era (n = 6,971) had significantly improved OS relative to those treated prior (n= 5,552) (HR 0.91, 95% CI 0.86-0.96, p < .001). However, patients treated during the pandemic who did not receive a COVID vaccine within 100 days of initiating ICI had nearly identical survival to those treated before the pandemic (HR 0.96, 95% CI 0.91-1.02, p = .1512). After controlling for covariables including ECOG performance status, histology, concurrent therapies, metastases, and comorbidities, patients who received SARS-CoV-2 mRNA vaccines within 100 days of initiating their first round of ICI had improved OS relative to those who did not (adj HR 0.75, 95% CI 0.69-0.81, p < .001). This relationship persisted when restricting the analysis to only those treated since the start of the pandemic era (adj HR: 0.76, 95% CI 0.69-0.84, p < .001). These survival effects were accentuated when the closest vaccine was received within 30 days of ICI initiation compared to 30-100 days (HR: 0.80, 95% CI 0.67-0.93). Similar survival benefits were not observed in patients with no COVID mRNA vaccination history who received flu vaccines (HR: 0.97, 95% CI 0.84-1.13, p = 0.74).Conclusions Improved outcomes following ICI treatment during the pandemic era are strongly associated with receipt of SARS-CoV-2 mRNA vaccines, but it appears that non-mRNA vaccines may not have similar effects. Future work should consider the impact of this relationship on immunotherapy trials performed since the pandemic.Ethics Approval IRB protocol number 2020-0348. IRB title: Data-Driven Determinants for COVID-19 Oncology Discover Effort (D3CODE). PI: Dr. Andrew Futreal.