It is well established that nonkeratinizing squamous cell carcinoma (SCC) of the oropharynx is causally related to transcriptionally active human papillomavirus (HPV) and has better survival as compared with carcinomas with a keratinizing phenotype (KSCC). Although the great majority of KSCCs are unrelated to HPV, transcriptionally active HPV is detected in a minority of oropharyngeal cases. To date, it has not been established whether the HPV status in KSCC also confers a survival advantage as it does in HPV-related nonkeratinizing SCC. This study compares clinical outcomes between patients with HPV-positive versus HPV-negative oropharyngeal KSCC. Among a total of 54 cases, 7 (13%) were diffusely and strongly positive for p16. HPV E6/E7 RNA was positive in 5 of the 6 (83%) p16-positive cases that were tested and in only 1 of the 47 (2%) p16-negative cases. Only 1 of the 7 (14%) p16-positive patients developed disease recurrence and died in the follow-up period. Kaplan-Meier survival analysis showed significantly better overall and disease-specific survival in the p16-positive than in the p16-negative patients (P=0.01 and 0.046, respectively). These data, although with relatively small patient numbers, suggest that HPV-related SCC in the oropharynx is associated with highly favorable outcomes, regardless of the keratinizing or nonkeratinizing phenotype.