PURPOSE: An important feature of malignant tumors is the disturbance in the balance between proliferation and cell death. We evaluated the relevance of intrinsic and radiation-induced apoptosis and proliferation for prognosis in rectal cancer patients. METHODS AND MATERIALS: Patients were selected from a study that randomized for preoperative radiotherapy (RT). Apoptosis and proliferation were scored using specific antibodies in immunohistochemistry. The number of positive cells per square millimeter of carcinoma cells was determined in 98 randomly selected tumors, of which 45 had been irradiated. For the survival analyses, a cohort of 104 patients without positive circumferential resection margins was selected. RESULTS: In nonirradiated patients, high levels of intrinsic apoptosis correlated with better local control (p = 0.04) and better cancer-specific survival (p = 0.02). RT increased the median amount of apoptosis from 10.8 to 21.5 cells/mm(2) (p = 0.004), but this was not predictive for survival. The amount of proliferative cells was not altered after RT and had no influence on prognosis. CONCLUSIONS: Intrinsic apoptosis correlated with both local control and cancer-specific survival, but proliferation was not predictive for prognosis. However, although RT increased apoptosis, its prognostic value was lost after RT. This is possibly because in rectal cancer, the proliferative status of tumors is always high and the aggressiveness of the tumor is determined by the number of "spontaneous" apoptotic tumor cells.