This report tests the hypotheses that cancer proneness elevates risk from a high radiation exposure and that the risk response to high doses is qualitatively similar to that from low doses. Groups of about 170 female mice heterozygous for Trp53 (Trp53 ^/−) and their normal female littermates (Trp53 ^/ ) were exposed at 7–8 weeks of age to ⁶⁰Co γ-radiation doses of 0, 1, 2, 3 or 4 Gy at a high dose rate (0.5 Gy/min) or 4 Gy at a low dose rate (0.5 mGy/min). In the absence of radiation exposure, Trp53 heterozygosity reduced life span approximately equally for death from either cancer or non-cancer disease. Heterozygosity alone produced a 1.5-fold greater shortening of life span than a 4-Gy acute exposure. Per unit dose, life shortening from cancer or non-cancer disease was the same for normal mice and Trp53 heterozygous animals, indicating that, contrary to previous reports, Trp53 heterozygosity did not confer radiation sensitivity to high doses of γ rays. In Trp53 ^/− mice with cancer, life shortening from acute doses up to 4 Gy was related to both increased tumor formation and decreased tumor latency. A similar tumor response was observed in normal mice, but only up to 2 Gy, indicating that above 2 Gy, normal Trp53 function protected against tumor initiation, and further life shortening reflected only decreased latency for cancer and non-cancer disease. Dose-rate reduction factors were 1.7–3.0 for both genotypes and all end points. We conclude that Trp53 gene function influences both cancer and non-cancer mortality in unexposed female mice and that Trp53-associated cancer proneness in vivo is not correlated with elevated radiation risk. Increased risk from high acute radiation doses contrasts with the decreased risk seen previously after low doses of radiation in both Trp53 normal and heterozygous female mice.