Background: Primary squamous cell carcinomas (SCCs) have diverse etiologies, but can share genomic features. We reviewed the genomic profiles of a series of SCC cases of differing anatomic origin. Methods: Hybrid-capture based genomic profiling of 182 or 236 or 315 genes was performed on 4783 squamous malignancies in the course of clinical care, with baits for HPV6, 11, 16, and 18, and assessment of tumor mutation burden (TMB; mutations/Mb) and microsatellite instability. Results: Sites of origin were head and neck (HNSCC, n = 1300), cervical (cSCC; n = 318), anal (aSCC, n = 248), esophageal (n = 242), lung (lSCC, n = 2386), and cutaneous (sSCC, n = 289) SCC cases. For HNSCC, cSCC, and aSCC (collectively termed HCA SCC), 395 (30%), 215 (68%), and 211 (83%) were HPV positive, respectively. For HCA SCC, the most common GA were in TP53 (45%), CDKN2A (29%), PIK3CA (24%), TERT (21%), and FAT1 (14%). The most frequent GA differentially associated with HPV status were in PIK3CA (34.9% versus 16.0%), CYLD (11.4% versus 1.4%) and PTEN (14.8% versus 6.1%) for HPV+ cases, and TP53 (3.8% versus 76.5%), CDKN2A ()1.4% versus 49.8%), and TERT (4.3% versus 33.0%) for HPV- cases. Mean TMB for HPV+ and HPV- cases were 6.6 (STDEV 7.3) and 13.7 (STDEV 29.7), respectively. TMB of all SCC cases was significantly different (p < 10^-12) when stratified by HPV status. For lSCC and eSCC, the most common GA were found in TP53 (86%) CDKN2A (40%), and PIK3CA (26%) and mean TMB was 11.6 with HPV found in 3.1% of cases. In sSCC, the most common GA were in TP53 (85.5%), CDKN2A (54.3%), and TERT(44.0%), and mean TMB was 59.5 with HPV in 3.1% of cases. Subsets of SCC cases had defining and targetable GA including bi-allelic deletion of SMARCB1 ( < 0.3%), amplification of PD-L1 (~2%), and various kinase fusions. Cases demonstrating radiologic response to immunotherapy and matched targeted therapies, as well as subsequent development of multiple mechanisms of acquired resistance, will be presented. Conclusions: HPV driven SCC have similar genomic profiles regardless of of site origin, and have a significantly lower median TMB than HPV negative SCC. Early consistency of responses of SCC to matched therapies may strengthen the case for site independent genomic predictors of therapy response.