Background: Immunotherapy has been increasingly used in cancer therapy. In rectal cancer, patients with high microsatellite instability (H-MSI) are candidates for immunotherapy, but there is little evidence on its effect on overall survival. Methods: A retrospective analysis of all patients with stage II-IV rectal adenocarcinoma in the US National Cancer Database (NCDB) between 2010 and 2019 was performed. Patients without data on whether or not they had immunotherapy were excluded. Propensity-score matching was used to adjust for baseline and treatment confounders and the cohort was divided into two groups: patients who received immunotherapy and matched controls. The primary outcome was overall survival. Secondary outcomes included 30-day readmission and 30- and 90-day postoperative mortality. Results: 5175/206,615 (2.5%) patients with rectal adenocarcinoma were treated with immunotherapy during the study period. Patients treated with immunotherapy were younger (58 vs 62 years; p < 0.001), more often male (64.4% vs 61.7%; p < 0.001) and had more private insurance (50.8% vs 43.4; p < 0.001) compared to controls. Patients treated with immunotherapy had more metastatic disease at presentation (clinical TNM Stage IV - 80.8% vs 23.3%; p < 0.001), presented with larger tumors (median: 5 vs. 4.2 cm; p < 0.001) and less often underwent surgery (33.7% vs. 69.9%; p < 0.001), radiation therapy (21.5% vs 57.4%; p < 0.001) and standard chemotherapy (38.1% vs 61%; p < 0.001). After matching, 488 patients were included in each group. Overall survival was significantly shorter in the immunotherapy group, with a mean survival of 56.4 months (95%CI – 53.03-59.86) compared to 70.5 months (95%CI – 66.15-74.92) in the control group (p = 0.004). Cox regression analysis of factors associated with overall survival demonstrated that, for the entire cohort, immunotherapy was associated with an increased mortality (HR 2.16; 95%CI: 2.09-2.24; p < 0.001). After stratifying based on clinical staging, immunotherapy was associated with improved overall survival in stage IV patients (HR 0.91, 95%CI 0.88-0.95; p < 0.001) but with lower survival in stage II (HR 2.38; 95%CI: 2.05-2.77; p < 0.001) and stage III (HR 2.43; 95%CI: 2.18-2.7; p < 0.001). Conclusions: Immunotherapy was associated with a modest increase in overall survival in patients with stage IV metastatic rectal cancer. However, overall survival was significantly lower in patients with Stage II-III disease when treated with immunotherapy.