Background: HNSCC can cause severe pain, exceeding the levels seen in other cancers. Opioids, the mainstay for cancer pain treatment, can have an immunomodulatory effect. We hypothesized that immunotherapy efficacy is impaired by immunosuppressive actions of opioids. Methods: We conducted a retrospective analysis of R/M HNSCC patients who received anti-PD-1 mAb therapy in the first line or platinum failure setting at UPMC Hillman from 2015–2020. Pretreatment (most recent visit prior to day of treatment) and day of treatment opioid prescription, calculated as morphine milligram equivalent (MME) per day, were evaluated. Opioids were analyzed as a continuous and a categorical (yes/no) variable. CD8 T and T regulatory (Treg) cells in the tumor microenvironment (TME) were evaluated on archival tumor samples via immunofluorescent imaging via ImageJ software. Linear regression and logistic regression were used to determine the effect of opioids on oncologic factors, disease control rate (DCR) and TME, depending on the data types. Univariable and multivariable Cox Proportional Hazard models were used to identify factors associated with progression free survival (PFS) and overall survival (OS). Results: The 66 patients analyzed were 79% male, median age was 67, 26% were HPV positive oropharyngeal, and 56% were platinum failure. The median time between pretreatment and day of treatment visits was 29 days. 63.3% of patients were on opioids pretreatment and day of treatment; median MME/day was 60 mg and 85 mg, respectively. When measured as a continuous variable, increased opioid dosage was significantly associated with worse PFS and OS at pretreatment (PFS, p = 0.002; OS, p < 0.001) and day of treatment (PFS, p = 0.021; OS, p = 0.017). Multivariate analyses, which included significant variables from univariate analysis (neutrophil/lymphocyte ratio (NLR), platinum failure) revealed that opioid dose given pretreatment (PFS, p = 0.047, OS p = 0.001) and day of treatment (OS, p = 0.019) are independently associated with worse survival. Receipt of pretreatment opioids, assessed as a categorical variable, were associated with a significant decrease in CD8+ T cells (p = 0.03), and on day of treatment, a significant decrease in CD8 T cells (p = 0.015) and the ratio of CD8 T cells to Treg (CD8/Treg, p = 0.011) in the TME. There was no correlation of opioid variables with DCR, PD-L1 expression, or NLR. Conclusions: In our analysis, opioids were associated with significantly lower PFS and OS as well as decreased CD8 T cells and CD8/Treg ratio in the tumor microenvironment. To our knowledge, this is the first study of the effect of opioids on the efficacy of anti-PD-1 mAb treatment for R/M HNSCC as well as on the TME. Our findings suggest the need for further study into the impact of opioids on immunotherapy efficacy to improve patient outcomes.