Background: PSCC patients (pts) with palpable inguinal lymph node (ILN) disease have a poor overall survival (OS). Multimodal perioperative treatments are usually offered despite the lack of clinically meaningful efficacy. Pending the availability of novel effective systemic therapy, the optimization of conventional treatments in better selected pts is needed. Methods: Within an international, multicenter database of 924 PSCC pts who received ILN dissection from USA, Europe, Brazil and China, 494 had information on HPV, and 52 (10.5%) had HPV+ PSCC, predominantly assessed with immunohistochemistry (53%). Multivariable logistic regression analyses evaluated the association between pt factors and HPV status. Multivariable Cox analyses (MVA) assessed predictors of overall mortality (OM), including HPV status, pathologically-involved ILN ratio (ILNR), extranodal extension, margin status, vascular invasion (VI), perioperative RT (pRT) and perioperative chemotherapy (pCT). Comparisons between HPV status and ILNR were performed using interaction tests. Kaplan-Meier method was used to define the OS benefit related in HPV-stratified sub-groups. Results: Median age at diagnosis was 58yrs. Overall, pCT and pRT were used in 227 (46%) and 50 (10%) pts. The median follow-up was 62 months. Neither clinical factors nor country were associated with HPV status. On MVA, ILNR (HR:1.01, p = 0.01) and extranodal extension (HR: 1.5, p = 0.02) were statistically significantly associated with OM, but HPV was not (p = 0.2). However, in the subgroup of pts who received pRT, HPV status was associated with favorable OM (HR: 0.11, 95%CI: 0.03-0.5, p = 0.004) together with negative VI (p = 0.03), and the use of adjuvant CT (p = 0.04). A significant interaction was found on OM between HPV+ status and increasing ILNR, with a cutoff at 50% (p = 0.05). Results are limited by their retrospective nature and small numbers in each subgroup. Conclusions: In the largest available dataset of ILND for PSCC, we observed that pRT seemed to be more effective in the subgroup of HPV+ PSCC. These results should be considered as hypothesis-generating and may inspire both the future prospective trials or the ongoing InPACT study.