The aim of this study was to determine whether caffeine enhanced radiosensitivity of normal liver tissue in a rat radiation-induced liver disease model. Buffalo rat McA-RH7777 hepatocellular cancer cells and BRL3A normal liver cells were irradiated, and cell cycle distribution and apoptosis rates were analyzed. A rat model of radiation-induced liver disease was established, rats were randomized into four groups: control; caffeine alone; irradiation (IR) alone; and caffeine plus IR (Caff + IR) group. Apoptosis rates in normal rat liver tissue after IR were evaluated by TUNEL staining and caspase-3 Western blot. Transaminase activity was measured and histopathological examination was done after IR. Caffeine abrogated IR-induced G2 phase arrest (Caff + IR vs. IR: 40.9 ± 4.0 vs. 60.7 ± 5.5%, at 12 h after IR) and increased apoptosis rates (Caff + IR vs. IR: 56.1 ± 6.8 vs. 35.5 ± 4.0%, at 72 h after IR) in McA-RH7777 cells, but did not affect IR-induced G2 phase arrest and apoptosis rates at any time point after IR in BRL3A cells. Caffeine did not enhance apoptosis, transaminase activity, or histopathological injury of normal rat liver tissue at any time points after IR. This study suggests that caffeine might not enhance radiosensitivity of normal liver tissue in vivo. In an earlier study, we reported that caffeine enhanced radiosensitivity of human hepatocellular cancer in a nude mice model. Together, these results offer feasibility of clinical application.