IMPORTANCE Second primary malignant neoplasms (SPMNs) are the leading cause of death in survivors of head and neck squamous cell carcinoma (HNSCC). Recently, human papillomavirus (HPV) has emerged as a risk factor for oropharyngeal squamous cell carcinoma and has different prognosis from classic tobacco/alcohol-associated HNSCC. This suggests that there also may be different risks and burden of SPMNs among patients who's HNSCC were from HPV or tobacco and/or alcohol. OBJECTIVE To assess SPMN risks and burden in a large US cohort of patients with a first potentially HPV-associated HNSCC vs non-HPV-associated HNSCC. DESIGN, SETTING, AND PARTICIPANTS In this population-based retrospective cohort study, 109 512 adult patients diagnosed with HNSCC between 2000 and 2014 were identified from the Surveillance, Epidemiology, and End Results registry. EXPOSURES HPV-relatedness based on whether patients' first HNSCC was potentially associated with HPV. Patients were grouped into 2 cohorts: potentially HPV-associated HNSCC, and non-HPV-associated HNSCC. MAIN OUTCOMES AND MEASURES The primary outcomewas incidence of SPMN (defined as the first subsequent primary cancer occurring at least 2 months after first cancer diagnosis). Excess SPMN risk was calculated using relative (standardized incidence ratios [SIRs]) and absolute (excess absolute risk [EAR] per 10 000 person-years at risk [PYR]). RESULTS A total of 109 512 patients with HNSCC (mean [SD] age, 61.9 [12.1] years; 83 305 [76.1%] men) were identified. The overall SIR was 2.18 (95%CI, 2.14-2.22) corresponding to 160 excess cases per 10 000 PYR. The risk among patients with first potentially HPV-associated HNSCC (SIR, 1.98; EAR, 114 excess cases per 10 000 PYR) was lower than those with first non-HPV-associated HNSCC (SIR, 2.28; EAR, 188 excess cases per 10 000 PYR). Overall, the largest SIRs and EARs were observed for cancers of the head and neck, lung, and esophagus. However, the risks of SPMN were lower among potentially HPV-associated HNSCC patients. CONCLUSIONS AND RELEVANCE Patients diagnosed with HNSCC experience excess risk of SPMN, which was higher among those with non-HPV-associated HNSCC than from potentially HPV-associated HNSCC. Clinicians should implement strategies that prevent or detect SPMN early in patients with HNSCC.