Background: Although SCC of the penile skin (pSCC) and the male urethral surface epithelium (uSCC) arise in nearby locations and can feature similar histology, their clinical manifestations, disease course, and surgical and medical treatment options are distinct. We performed CGP on pSCC and uSCC to examine genomic profiles differences. Methods: Tissues obtained from men with clinically advanced pSCC (n = 230) and uSCC (n = 17) underwent hybrid capture-based CGP to evaluate all classes of genomic alterations (GAs). Tumor mutational burden (TMB) was determined on up to 1.1 Mb of sequenced DNA and microsatellite instability (MSI) was determined on up to 114 loci. PD-L1 expression was determined by IHC (Dako 22C3). Results: The median ages were similar in both groups. pSCC exhibited a slightly higher frequency of HPV-16/18 infection (29% vs. 12%, P = .16), although the TP53 mutation frequencies were nearly identical (55% vs. 59%, NS). CDKN2A inactivation (P = .08), CCND1 amplification trending higher and TERT promoter mutations (P = .01) were more frequent in pSCC, potentially indicating prior HPV infection. GAs in NOTCH1 were exclusively identified in pSCC. Potentially actionable GAs identified in both groups included PIK3CA activating mutations (TKIs) as well as pathogenic alterations in FBXW7 and PTEN (MTOR inhibitors). Rare BRCA1 and BRCA2 inactivation (PARP inhibitors) was seen in pSCC only. High-positive PD-L1 staining was elevated in pSCC (34 vs. 14%, P = .06). Although average TMB was similar in both groups, pSCC exhibited an elevated frequency of cases with CD274 (PD-L1) amplification as well as TMB >10 mut/Mb which are on label for immune checkpoint inhibitor (ICPI) treatment. Conclusions: CGP of pSCC and uSCC identifies opportunities for both targeted and ICPI therapies. Compared to uSCC, pSCC had genomic features more similar to head and neck SCC including slightly increased cell-cycle perturbation, HPV infection, and NOTCH pathway signaling alterations. Further use of CGP in the treatment planning for pSCC and uSCC may be warranted.