Daily fractions of 188, 250, 375, 500, and 750 rads were given to rats with hepatoma 3924A so that all groups received the same weekly dose of 1500 rads over a 6-week period, for total doses of 9000 rads when only radiation was given and 4500 rads when combined with cyclophosphamide. No tumors were cured (with two exceptions) with or without three doses of cyclophosphamide (150 mg/kg or 0.9 g/sq m) given 14 days apart. The addition of cyclophosphamide to the daily radiation treatment schedules did not change the time for tumors to reach 8 times the volume at time of treatment but did result in a longer median survival, which was attributed to a reduction of pulmonary metastases. A hyperfractionated radiation schedule using six 250-rad fractions given three times daily every 4 hr for 2 days combined with cyclophosphamide (150 mg/kg) 1 day later and repeated two additional times at 11-day intervals for a total dose of 4500 rads and cyclophosphamide (450 mg/kg) resulted in eradication of six of ten tumors, for a cure rate of 60%. Skin damage, determined by visually scoring the skin, appeared to be fully recovered by Day 126 and remained so until the end of the experiment on Day 384. The three courses of hyperfractionated radiation (total dose, 4500 rads), when given alone, were ineffective in producing tumor regression and cure. Combining cyclophosphamide with hyperfractionated split-course radiation schedules gave a major increase in tumor cure rate as compared with radiation alone at the same (4500 rads) or higher (9000 rads) doses. The major gains in effective utilization of the two modalities is greatly diminished or lost when the radiation is administered as daily fractions.