© 2019 Elsevier Inc. Our objective was to evaluate the pathologic features and clinical outcomes in cases of invasive penile squamous cell carcinoma (SCC) and the association with p16 immunohistochemistry (IHC) and human papilloma virus (HPV) in situ hybridization (ISH). A retrospective multi-institutional database search was conducted for invasive SCC of the penis diagnosed between 2007 and 2018 that had undergone surgical resection. Pathologic features, p16 IHC, and HPV ISH were investigated with clinical outcomes. A total of 102 patients were included in the study. The average age was 63 ± 13.3 years. Based on histology, 46% of tumors displayed an HPV-related subtype, whereas p16 was positive in 52% of all cases. Tumor histology correlated well with p16 positivity (P <.001), and p16 IHC accurately predicted the presence of HPV in 25/26 (96%) cases. On multivariate analysis, perineural invasion was associated with local disease recurrence (P =.02), whereas lymphovascular invasion was associated with progression to metastatic disease (P =.002) and increased overall mortality (P =.02). Urethral involvement was also associated with increased overall mortality (P =.02). In addition, HPV-related tumors based on histologic features correlated with lower rates of metastatic disease (P =.007). HPV is a common cause of penile SCC and can be diagnosed by tumor histology and confirmed by overexpression of p16 on IHC. The presence of lymphovascular invasion, perineural invasion, and urethral involvement are poor prognostic indicators, whereas HPV-related tumors based on histology may have lower risk for metastatic disease.