Background/Objectives: Cutaneous squamous cell carcinoma (cSCC) harbors one of the most mutated genomes. There are limited data on the genomic profile and its predictive potential for response to immunotherapy with PD-1 inhibitors in cSCC. Methods: This study retrospectively reviewed cSCC patients treated with PD-1 inhibitor monotherapy at a single institution. Clinical characteristics, treatment outcomes, PD-L1 expression, tumor mutation burden (TMB), and genomic profile in tumor and blood were analyzed. Logistic regression and a support vector classifier were used to validate identified biomarkers of significance. Results: Twenty-five patients were evaluable for response and had genomics tested in tumor and/or blood. Of the total, 80% of patients achieved an objective response: 40% complete response (CR), 32% partial response (PR) for more than 6 months, and 8% stable disease (SD) for more than 1 year; 20% of patients progressed on treatment. With a median follow-up of 21 months, progression-free survival (PFS) was 28 months in responders vs. 3 months in non-responders (p = 0.00001). Median PD-L1 was 25% in responders vs. 10% in non-responders (p = 0.39). There was no difference in median TMB between responders and non-responders. Eight gene mutations were significantly more frequent in non-responders than in responders: CDK12 (p = 0.005), CTCF (p = 0.033), CTNNB1 (p = 0.033), IGF1R (p = 0.038), IKBKE (p = 0.016), MLH1 (0.033), QKI (p = 0.016), and TIPARP (p = 0.033). A support vector model of these genes classified responders and non-responders with an accuracy of 0.88 in the training data and 1.0 in the testing data. Conclusions: PD-1 inhibitor monotherapy produces an impressive response. Eight gene mutations were significantly more frequent in non-responders. PD-L1 and TMB were inconclusive in predicting treatment response to anti-PD-L1.