OBJECTIVE: To evaluate the independent effects of caloric restriction (CR) and body weight (BW) on mortality rate (MR) and the extent to which BW may mediate the effect of CR on MR. DESIGN AND SUBJECTS: Data were from the Biosure Study, a randomized, controlled, prospective intervention study of diet regimens in 1200 Wistar rats. Animals were followed until they died spontaneously, were euthanized because of illness, or reached age 30 months. STATISTICAL ANALYSIS: Cox regression was performed to evaluate the effects of CR and BW on MR. Bootstrap procedures were used to test the contribution of BW to the effect of CR on MR. RESULTS: CR initiated after age 13 weeks decreased the rate of subsequent mortality. The MR increased with higher BW in early adulthood (21 weeks) and this effect persisted even after adjustment for CR. After adjustment for BW in early adulthood, we did not find a similar relation between mortality and BW in late adulthood (105 weeks). Mediation analysis indicated that low BW associated with CR appeared to mediate some of the mortality-reducing effects of CR, but CR clearly had effects independent of BW. The reductions in BW appeared to account for approximately 11% of the effect of CR. CONCLUSION: CR and BW have independent effects on MR in Wistar rats. BW may mediate a small part of the CR effects on MR.