BACKGROUND: Second primary malignancies (SPMs) are the leading cause of death in survivors of head and neck squamous cell carcinoma (HNSCC). Synchronous SPMs are of significant clinical interest because they potentially can be identified by screening procedures at the time of diagnosis of the index cancer. Recently, human papillomavirus (HPV) has emerged as a distinct risk factor for oropharyngeal head and neck squamous cell carcinoma (HNSCC), differing from classic tobacco/alcohol-associated HNSCC, suggesting that there also may be distinct patterns of synchronous SPMs. METHODS: The authors performed a population-based cohort study in 64,673 patients in the National Cancer Institute Surveillance, Epidemiology, and End Results registry (1979-2008), defining risks of synchronous SPM in patients with HNSCC who were diagnosed before and after the emergence of prevalent HPV-associated oropharyngeal HNSCC. Excess risk was calculated using standardized incidence ratios (SIR) and excess absolute risk per 100 patients. RESULTS: Among patients with HNSCC, the SIR of synchronous SPM was 5.0, corresponding to 2.62 excess cases per 100 patients. The site with the highest excess risk of a second cancer was the head and neck (SIR, 41.4), followed by the esophagus (SIR, 21.8), and lung (SIR, 7.4). The risk of synchronous SPM changed markedly over time for patients with oropharyngeal HNSCC. In the 1970s and 1980s, oropharyngeal cancers carried the highest risk of SPM. Risk began to dramatically decline in the 1990s; and currently, oropharyngeal cancers carry the lowest risk of synchronous SPM. CONCLUSIONS: The current data are consistent with the etiologic shift of oropharyngeal HNSCC, from a primarily tobacco-associated malignancy associated with significant field cancerization of the upper aerodigestive mucosa, to a malignancy primarily caused by oncogenic human papillomavirus.