Undifferentiated carcinoma (undifferentiated carcinoma, nasopharyngeal type, or lymphoepithelial carcinoma) is an uncommon and histologically distinct tumor in the oropharynx, which in Western countries, has been clearly shown not to harbor Epstein Barr virus (EBV). We sought to analyze these tumors for human papillomavirus (HPV) and to examine their clinical outcomes. All cases of oropharyngeal carcinoma diagnosed as 'undifferentiated' or 'lymphoepithelial' were retrieved from the department files at Barnes-Jewish Hospital. After consensus review by all three study pathologists, 16 were found to have diagnostic histological features and to lack distinguishing characteristics of other oropharyngeal cancers. Immunohistochemistry for p16 and p53 and in-situ hybridization for HPV and EBV encoded small RNA were performed. p16-positive but HPV in situ hybridization-negative cases were analyzed by polymerase chain reaction for high-risk HPV types. The results were correlated with pathological findings and clinical follow up. There were 16 patients. The average age was 59.2 years, 14 patients (88%) were smokers, and 13 (81%) had nodal metastases. In all, 14 cases (88%) were p16 positive and 15 (94%) were HPV positive by in situ hybridization and/or polymerase chain reaction. All cases were negative for EBV, and p53 was overexpressed in five (33%), four of which were HPV positive. Disease recurred in only three patients and two of these died with disease at 38 and 136 months, respectively. Three year overall, disease-free, and disease-specific survival rates were 54, 78, and 100%, respectively. In summary, in our patient population, the majority of oropharyngeal undifferentiated carcinomas harbor transcriptionally active HPV but not EBV. Almost all overexpress p16, and few have p53 overexpression. Disease-specific survival is comparable to published rates for other HPV-related oropharyngeal squamous cell carcinoma variants and is better than that of HPV-negative carcinomas.