Background: HPV (human papillomavirus) and HIV (Human Immunodeficiency Virus) are risk factors for Penile cancer (PC); HIV-HPV co-infection heightens the risk of anogenital dysplasia (PMID: 19706632, 19082746, 35630489). However, there is paucity of data on the impact of HIV-HPV co-infections on PC outcomes. We evaluated the characteristics, outcomes, and healthcare utilization of patients with PC with and without HIV-HPV co-infection (HHC) from a national sample. Methods: Healthcare Cost and Utilization Project-Nationwide Inpatient Sample database was queried to identify all PC patients with (HIV-HPV-PC) and without HIV-HPV co-infection (non-HIV-HPV-PC) from 2016-2020. The groups were compared for socio-demographic differences, medical comorbidities, inpatient mortality, length of stay (LOS), and total hospital charges (THC). Secondary outcomes included rates of sepsis, septic shock, and UTI. Statistics were performed using t-test, univariate and multivariate logistic regression. Results: Out of 11,320 PC admissions, 255 had HIV, 205 had HPV, and 30 had HIV-HPV co-infection. Patients without the co-infection were older with a mean age of 65.6 years as compared to those with HIV-HPV co-infection, who had a mean age of 52.7 years (p = 0.002). Compared to non-HIV-HPV-PC, HIV-HPV-PC patients were more likely to be Black (66.7% vs 11.3%, p<0.001). The prevalence of comorbidities was similar between both groups. HIV-HPV co-infection in penile cancer patients was associated with a ten-fold higher adjusted all-cause mortality compared to those without the co-infection (adjusted odd ratio (aOR) = 10.2, p = 0.035). Mean LOS (6.0 vs 5.7 days, p = 0.8) and THC ($65,472 vs $64,627, p = 0.32) were similar between cohorts. Conclusions: HIV-HPV co-infection in penile cancer is associated with younger age, black race, and a ten-times higher adjusted all-cause inpatient mortality.