Background: Nodal metastases from SCC are a clinical challenge in urologic and gynecologic oncology. Strategies employing CGP to identify targeted therapies for CUPs have shown potential; however, the molecular landscape of SCCUP remains poorly defined. We report the results of CGP testing in patients with SCCUPs identified in the Foundation Medicine, Inc. database, with a focus on those with I/P/RP involvement. Methods: SCCUP cases with FoundationOneCDx (F1CDx) assay results were identified based on a reported diagnosis of CUP and the presence of SCC histology. After central pathologist review, cases were excluded if a known primary site could be determined based on histology and disease location. Cases with I/P/RP involvement were selected based on the site of tissue biopsy. Genomic alterations (GAs) were assessed using the FoundationCORE database. Results: Ninety-seven cases of SCCUP presenting with I/P/RP involvement were identified. GAs were observed in 140 of 324 genes evaluated by the F1CDx assay. The most frequently altered genes were PIK3CA (38.1%), TP53 (37.1%), KMT2D (23.7%), PTEN (21.6%), and CDKN2A (19.6%). The most frequently altered potentially actionable GAs were in PIK3CA, PTEN, FGFR3 (9.1%), MTAP (7.2%), BRCA1 (5.2%) and BRCA2 (5.2%). One patient had microsatellite instability high disease, while 27 (27.8%) had a tumor mutational burden ≥ 10 mut/Mb. Of 54 evaluable patients, 18 (33.3%) had high-positive PD-L1 expression. Two patients (2.1%) had TMPRSS2-ERG fusions supporting occult prostate cancer, while 13 (13.4%) had UV light exposure signatures suggesting unrecognized cutaneous origin. No significant differences in GAs were observed between 64 patients with inguinal disease and 33 patients with pelvic and retroperitoneal disease. An additional 346 cases of SCCUP were identified with involvement outside of the I/P/RP. Compared to these patients, those with I/P/RP involvement were more likely to be female (64% vs 42%,odds ratio [OR] 2.46, p=0.001), and were less likely to have mutations in CDKN2A (19.6% vs 41.9%, OR 0.34, p=0.002), TP53 (37.1% vs 69.7%, OR 0.26, p<0.001), and KRAS (2% vs 12.7%, OR 0.14, p=0.02). Patients with I/P/RP disease were also more likely to have evidence of HPV infection (54.6% vs 14.4%, OR 7.1, p<0.001) and APOBEC mutation signatures (70% vs 18.7%, OR 10.1, p<0.001), which have been associated with viral infection. Conclusions: Fifty-three of 97 (54.6%) patients with SCCUPs presenting with I/P/RP involvement had at least one GA that could potentially guide targeted treatment decisions including entry into biomarker-driven clinical trials. I/P/RP SCCUP patients frequently demonstrated HPV infection and APOBEC mutation signatures. To our knowledge, this is the first report that describes the genomic landscape of SCCUPs presenting with I/P/RP metastases.