This study was conducted to determine whether Bcl-2 overexpression in localized squamous cell carcinoma of the head and neck (SCCHN) might serve as a marker for tumors unlikely to respond to standard treatment. Tissue samples from 33 patients undergoing surgery or irradiation for early-stage SCCHN during the year 1977 to 1992 were stained for Bcl-2. All patients had either T1N0 lesions of the oral cavity, pharynx, or larynx or T1N0 or T2N0 lesions of the true vocal cords. Of the 33 patients, 26 remained disease-free after at least 3 years of follow-up; the remaining 7 patients developed either tumor recurrence or a second primary tumor, 4 of which were fatal. Twelve patients had tissue specimens staining positive for Bcl-2; 6 of these patients had a poor outcome, and 6 had a good outcome. The relationship between poor outcome and overexpression of Bcl-2 in tumor cells was statistically significant (p = .0047 by Fisher's exact test). For tumors overexpressing Bcl-2, there was no significant difference in recurrence rate between those undergoing surgery and those undergoing radiotherapy as the primary mode of treatment. The overexpression of Bcl-2 in early lesions in this study predicted a cure rate of 50%, as opposed to the generally expected 90%, suggesting that Bcl-2 is a significant prognostic indicator in early SCCHN. Future studies will determine if altering the treatment will improve outcome in these patients.