A meta-analysis was performed on data from the Washington University Department of Otolaryngology Head and Neck Tumor Registry and 24 studies reporting synchronous and metachronous malignancies in head and neck cancer patients. The overall second malignant tumor (second primary) prevalence was 14.2% in 40,287 patients, the majority of tumors being metachronous. Site relationships between index tumors and second primaries revealed significantly high risks along the digestive tract axis or the respiratory tract axis, although lung second primaries were prevalent in all groups. Head and neck second primaries were the largest group, being significantly more common in the oral cavity, oropharynx, and hypopharynx than in the larynx. Oral cavity index tumors showed the highest overall rate of second primary formation. Half of all aerodigestive tract second primaries are detected by 2 years from index tumor presentation, but non-aerodigestive tract tumors are common beyond 5 years. A significantly higher detection rate was proven for the prospective panendoscopy studies. We recommend routine interval endoscopic intervention within 2 years of treatment for optimum detection of second primaries in head and neck cancer patients. Also, a lifetime of clinical surveillance is suggested for aerodigestive tract second neoplasms in oral cavity, oropharynx, and hypopharynx cancer patients and for lung and non-aerodigestive tract neoplasms in larynx cancer patients.