Total radiation (4500 rad) and cyclophosphamide doses (450 mg/kg or 2.7 g/m2) were held constant over a 24-day period in rat hepatoma 3924A using radiation schedules in which 1500 rad were given over a 1-to 2-day period in 1-8 fractions, repeated at ll-day intervals, with or without cyclophosphamide. Reducing the rad per fraction resulted in a reduced incidence of complete tumor response and tumor cures, and a reduction in the magnitude of skin response. Cure rates were 40, 10, 0, and 0%, respectively, for the 1500, 750, 500, and 250 rad per fraction groups without cyclophosphamide. When the 1500, 750, 500, 375, 250, and 188 rad per fraction groups were given 150 mg/kg cyclophosphamide day 1 after radiation, major increases occurred in tumor cures, with the cure rates being 80, 80.80, 70,60, and 5076, respectively. The addition of cyclophosphamide did not significantly alter skin reaction to radiation. The higher rad per fraction schedules were more effective in controlling metastatic dissemination when radiation was used alone. The addition of cyclophosphamide markedly reduced metastatic dissemination in both high and low-dose per fraction schedules. Optimal treatment levels were estimated from analysis of fitted response surfaces, and the quantitative interrelationship between normal tissue reaction, probability of tumor cure, and associated relative hazard to the host estimated from the results of these analytical methods. Hyperfractionated radiation dose schedules with dose/fraction in the clinical range combined with cyclophosphamide can significantly increase the therapeutic ratio and prevent metastatic dissemination compared with radiation alone as a result of the increased effectiveness of combined modality therapy on the tumor, without a concomitant increase in normal tissue reaction.