The effects of two methylxanthines, caffeine and isobutylmethylxanthine (IBMX), on the response to radiation given at two low dose rates were studied in a human hepatoma cell line, HepG2. These dose rates are in the range to which tumor cells are exposed in radiolabeled immunoglobulin therapy of primary hepatoma. At the higher dose rate (0.3 Gy/hr for 24 hr), the radiation completely inhibited growth, and cells accumulated in the G2 phase of the cell cycle. Caffeine (1 mM), given either continuously or during the last 4 hours of the radiation exposure, counteracted the growth inhibition and G2 accumulation and enhanced cell killing. The 0.5-mM dose of IBMX had little effect on cells. For a lower dose rate and longer exposure period (0.06 Gy/hr for 3 days), the radiation partially inhibited growth and the accumulation of cells in G2 was small. Continuous, but not short, exposure to caffeine enhanced killing at this dose rate and counteracted the G2 accumulation. At the lower dose rate, IBMX enhanced the growth inhibition, G2 accumulation, and killing above that with radiation alone.