To assess the prognostic value of apoptosis, proliferation and clinical factors in squamous cell carcinoma of the oropharynx after radical surgery and postoperative radiotherapy (RT). Between 1985 and 1995, a total of 82 patients with 84 tumors were entered onto the study. Forty-two primary tumors (50%) involved the tonsils, 23 (27%) the soft palate, and 19 (23%) the base of the tongue. Median age was 52 years (range, 36-73 years). The pT- and pN-categories (UICC 1997) were: T1 (24), T2 (36), T3 (18), T4 (6), N0 (31), N1 (12), N2 (38), NX (8). Histologically clear margins were achieved in all patients by initial surgery. Postoperative RT to the primary and regional lymphatics was given with 60 Gy in 6 weeks and single daily fractions of 2 Gy. The expression of the nuclear Ki-67 labeling index (LI) was investigated by immunostaining using the monoclonal antibody MIB 1 and apoptotic carcinoma cells were identified using the terminal deoxynucleotidyltransferase-(TdT)-mediated dUTP nick end labeling (TUNEL) technique. Median follow-up was 43 months (range, 14-132 months). Overall survival, disease-free survival, and locoregional tumor control rates were 59, 70 and 76% at 5 years. Median values for apoptotic index and Ki-67 labeling were 1.6% (range 0-4.7%), and 20% (range, 0-79%), respectively. Apoptotic index <or=1.6% had a profound negative impact when associated with higher proliferation rates (5-year disease-free survival: 26%) as compared to all other patients with a balance between apoptosis and proliferation (5-year disease-free survival: 66-86%, P=0.003). Additional significant prognostic factors for disease-free survival were: tumor site (tonsils: 83% vs soft palate: 66% vs base of tongue: 49%, P=0.02), duration of RT (<or=47 days: 83% vs >47 days: 55%, P=0.03), Ki-67 LI (<or=20%: 84% vs >20%: 56%, P=0.006). A significant prognostic impact on locoregional control was noted for the duration of RT (P=0.01), tumor site (P=0.02), and the Ki-67 LI (P=0.02). A low apoptotic index together with higher proliferation rates led to unfavourable local control as low as 25% compared to the patients with higher apoptotic index (70-80%, P=0.009). An imbalance between apoptotic index and proliferation may identify patients with squamous cell carcinoma at high risk for local recurrence after surgery and postoperative RT. Prospective observation of these factors in clinical trials is warranted to further elucidate this phenomenon.