Second primary malignancy (SPM) is the major long-term cause of patient mortality with head and neck squamous cell carcinoma (HNSCC). As the incidence of high-risk human papillomavirus (HPV)-related HNSCC is increasing globally, we analyzed the patterns of SPM occurrence, the effect of the index tumor site along with attributes to HPV, and the effect of SPM on survival in South Korean patients with head and neck cancer (HNC). Data were retrieved from the Korea Central Cancer Registry, a nationwide population-based cancer registry, from 1993 to 2010. Standardized incidence ratios were analyzed and compared between index tumor sites, particularly oropharyngeal vs. non-oropharyngeal sites. After adjustment for competing risks, 3- and 5-year SPM rates were calculated using the cumulative incidence function. The effects of SPM occurrence on overall survival (OS) were then analyzed. SPM rates were significantly lower for HPV-attributable oropharyngeal sites than for non-oropharyngeal sites, such as the larynx and hypopharynx (p<0.001). SPM rates were also lower for oral cavity first primary sites than for non-oropharyngeal first primary sites (p<0.001). SPMs typically occurred in the esophagus, lungs and the head and neck. Uterine cervical cancers occurred significantly more frequently after index oropharyngeal cancer in women. The 5-year and 10-year OS rates were 57.8 and 45.7% in all HNC patients, respectively. The OS after SPM occurrence was poor (5-year, 31.8%; 10-year, 20.8%) compared to after index HNC occurrence (5-year, 68.4%; 10-year, 41.2%). SPM occurrence in the esophagus and lung/bronchus showed a worse OS than SPM localized to the head and neck. South Korean HNC patient, the first primary cancer site affected SPM risk and distribution. The 5- and 10-year OS rates deteriorated after SPM occurrence, particularly in the esophagus and lungs. Further optimization of follow-up strategies for effective surveillance of SPM, particularly in the esophagus and lungs, is warranted.