Background: Immune checkpoint inhibitors (ICI) are monoclonal antibodies that promote immune recognition of tumor cells to facilitate their elimination. Opioids are a major facet of pain management in cancer patients. Since chronic opioid use results in immunosuppression, the purpose of this study was to evaluate the survival outcomes of cancer patients on concurrent ICI and opioid therapy. Methods: This single-institute retrospective study from an NCI-designated comprehensive cancer center evaluated all patients in the primary or recurrent setting who underwent ICI therapy (anti-PD-1/PD-L1/CTLA-4) from 1 January 2020 to 18 June 2021. Demographic, clinicopathologic, and co-morbidity data were obtained from electronic medical records and the New York State Cancer Registry data. The New York State Prescription Monitoring Program was used to collect data about opioid prescriptions filled by patients from 30 days prior to and 30 days after the end of ICI therapy. Patient characteristics were analyzed with the Mann-Whitney U or chi-square tests. Survival analyses were performed using the Kaplan-Meier and Cox model regression, adjusting for relevant clinical factors. Results: A total of 869 patients were evaluable based on inclusion criteria and data availability. Most patients (77.15% chronic users and 64.62% occasional users) had stage III/IV disease. The most represented services included: gynecology (11.54%), soft tissue/melanoma (14.13%), thoracic (38.75%), urology (11.9%). Comorbidities did not vary between the two groups. Pre-treatment median opioid consumption was higher in the chronic users compared to occasional users (240 oral morphine equivalents (OME) vs 120, p = 0.03). Total opioid prescriptions filled was significantly higher for chronic users compared to occasional users (4275.0 vs 520.1 OME, p < 0.001). Chronic users were more likely to be on an additional anti-neoplastic agent (64% vs 44.07% for occasional users). Occasional users had significantly longer progression free (44.7 vs 16.0 months, p < 0.001) and overall (42.7 vs 16.2 months, p < 0.001) survival. When controlling for age, stage, and concurrent therapy, chronic opioid use retained a significantly negative association with PFS and OS. Conclusions: Patients on ICI therapy in the primary and recurrent setting who chronically use opioids exhibit significantly decreased PFS and OS compared to the occasional user cohort. This study provides evidence that chronic opioid use during ICI therapy results in inferior clinical outcomes.