OBJECTIVE To analyze serial measurements of squamous cell carcinoma antigen (SCCAg) to determine its prognostic significance in squamous cell carcinoma of the head and neck (SCCHN). METHODS Retrospective analysis of serial SCCAg measurements in 75 patients with squamous cell carcinoma of the head and neck. Serum samples were obtained preoperatively and at postoperative intervals ranging from 1 week to 36 months. Serum SCCAg levels were determined by radioimmunoassay. METHODS Oncologic head and neck practice at a tertiary referral hospital. METHODS Tumor Registry data of 75 consecutive patients with at least three postoperative SCCAg determinations were reviewed to provide equal numbers of patients with and without recurrent disease. All patients who remained disease-free were followed up for at least 2 years. All patients were previously untreated and underwent surgical therapy. METHODS Association of postoperative SCCAg levels and 2-year disease-free survival. RESULTS No differences in preoperative levels were noted, but SCCAg levels predicted 2-year disease-free survival at 6, 9, and 12 months after surgery. The ratio of post-operative SCCAg levels to preoperative and early post-operative levels also provided prognostic information. CONCLUSIONS Serial measurements of SCCAg postoperatively in patients with head and neck cancer predict outcome and may allow for earlier detection of recurrent disease. Further studies are needed to determine if earlier detection can be translated into improved survival.