Water deprivation for 48 hr with its accompanying decrease in food intake significantly lowered the in vitro rate of hexobarbital metabolism by hepatic microsomes isolated from male rats. Pair‐fed rats allowed waterad libitumhad a significantly lower level of hexobarbital metabolism than those deprived of water. Rats starved for 24 hr with or without water also had levels of hexobarbital metabolism significantly lower than their controls; with those animals allowed water ad libitum, the level was significantly lower than for those deprived of water.In vivohexobarbital “sleeping time” experiments were in general agreement with these results. The in vitro metabolism of aniline was increased in both male and female rats following 24 hr starvation and in female rats (but not males) the effect was greater when water was allowed than when deprived. The differences between hydrated and dehydrated animals were not attributable to reduction in concentration of microsomal protein or the water content of liver. It is concluded that water consumption accentuates the effect of food deprivation on hepatic microsomal metabolism.