Immunosuppression is a strong risk factor for cutaneous squamous cell carcinoma (cSCC). Immunosuppression is also associated with unique mutagenic stressors that likely contribute to cSCC pathogenesis. However, it is unknown whether these stressors contribute to a distinct mutation profile that may drive disease progression. This review was conducted to assess the mutational landscape of cSCC arising in immunosuppressed hosts. Specifically, we sought to determine gene mutation frequencies in immunosuppressed cSCC. An electronic search was performed in PubMed, Embase, Scopus, and Cochrane databases. Studies performing DNA sequencing or genotyping of cSCC were identified. Studies were excluded if the immune status of each tumor was not available. Eighteen studies met inclusion criteria. Due to study heterogeneity a meta-analysis was unable to be performed. However, statistical analysis was performed on the most frequently reported genes. NOTCH1 was the most frequently mutated gene in immunosuppressed cSCC, and was significantly higher than immunocompetent cSCC after multiple comparison adjustment (77.7 versus 58.1%, OR 2.50, 95% CI 1.40-4.46, p=0.002). No other statistically significant differences were observed. Our results suggest that NOTCH1 mutations are more common in cSCC arising in immunosuppressed hosts. Several prior observations reviewed here further support a role for NOTCH1 in immunosuppressed cSCC, however larger studies are needed to confirm our findings.