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The effect of diet, age and time of dose delivery on the mortality of female B6C3F1 mice from ganciclovir sodium (DHPG) was determined for both single (SD; 400 mg DHPG/kg, ip) and multiple doses (MD; same dose ip for 10 additional days) of the drug. Young (7-10 months) and middle-aged (MA; 19-22 months) mice (B6C3F1), both fed ad lib. (AL) and calorie restricted (CR), were dosed at 0, 6, 12 and 18 hr after lights on (HALO; SD study) and at 12.00 hr (MD study). The SD study mortality rate was 38% (AL) and 1.7% (CR) (P < 0.00001). Mortality was 53% (AL, young; P < 0.00001), over 20% (AL, MA), over 1.8% (CR, MA; P = 0.00004) or more than 1.7% (CR, young; P = 0.00002). Effects were independent of lean body mass differences between AL and CR mice. In the SD study, comparing AL mice only, the greatest mortality was seen in young mice at 6 HALO, (73%; P = 0.0034) and lowest mortality in MA mice at 12 HALO (8%; P = 0.026), whereas in the MD study mortality was 63% AL and 33% CR (P = 0.015). By age, MD mortality was 80% (AL, young; P = 0.0035), 50% (CR, MA), 47% (AL, MA), and 15% (CR, young; P = 0.0013). CR protected both young and MA mice in SD and young mice in MD. Lowest mortality for AL was at 12 HALO. It is suggested that dosing at 12 HALO may protect by decreasing DHPG uptake during a period of minimal DNA synthesis in the affected organ(s). CR and timing of DHPG dose may obviate the necessity to discontinue DHPG because of toxicity in humans. The most significant finding of this study is the impact of diet on mortality.