Multiple primary tumors are a known phenomenon in head and neck cancer. They are partially responsible for the limited improvement in survival of head and neck cancer during the past 20 years. Only a few prospective data have been published about the incidence of metachronous tumors. The authors prospectively studied 127 patients with squamous cell carcinoma of the head and neck. The overall incidence of second primary tumors was 13.5% (simultaneously, 3%; synchronously, 5.5%; and metachronously, 8%). More than 90% of the recurrences of the first primary tumor occurred within the first 2 years following primary treatment, but the second primary tumors continued to occur gradually in the course of follow-up. Most of the second primary tumors were discovered because the patients developed symptoms (14/17). Survival after detection of the second primary tumor was poor. The development of a second primary tumor was of equivalent prognosis to a recurrence of the primary tumor. Future directives include the development of more adequate screening methods. Identification of potential early markers for the development of a squamous cell carcinoma at the level of the mucosa at risk and in serum could be of value for the early detection of individuals at risk.