Long-term caloric restriction extends lifespan, probably through a reduction in radical production and attenuation of oxidative stress. In addition, caloric restriction is associated with a reduction and incidence in tumor pathology, probably, in part, via an enhanced rate of apoptosis. We examined whether short-term (2-month) caloric restriction (40% reduction compared to ad libitum controls) increased hepatic apoptosis and if this was associated by an enhancement in various proteolytic caspase (-3, -7, -9, -12) levels and/or a decrease in two potential inhibitors of apoptosis (the x-linked inhibitor of apoptosis protein XIAP and heat shock protein 70). Short-term caloric restriction resulted in a significant decline, compared to ad libitum controls, in both body mass (30%) and liver mass (46%). While hepatic apoptosis (DNA fragmentation) was significantly higher in the caloric restricted rats, this was not associated with any increase in caspase (-3, -7, -9, -12) levels in the liver. Indeed, the levels of caspase-3, -7 and -12 were significantly lower in the caloric restricted group compared to the ad libitum controls and no differences were observed between groups in either XIAP or HSP70 levels. These findings suggest that enhanced hepatic apoptosis observed after 2-months of caloric restriction is not a result of elevated caspase levels at this time, thereby suggesting that an alternative, caspase-independent pathway may be involved.