Phenobarbital elicits a hypothermic effect in rats. To determine if functional tolerance develops to this effect on temperature, rats were treated twice daily with IP injections of sodium phenobarbital (PheB) or saline. The PheB doses were increased over 21 days and then were held constant for another 23 days. On the next day (day 45) animals from both groups were given 80, 110 or 160 mg/kg PheB IP and the decrease in rectal temperature after 2 h was determined. Animals were decapitated after the temperature measurement and brain PheB levels were determined. A 1.51-fold shift in the relationship between brain level and response was found for the group given chronic PheB. These results show functional tolerance occurs to the hypothermic effect of PheB. This experiment was done in animals that were on a restricted food regimen. Rats given chronic PheB lost more weight than the group given chronic saline unless extra food was provided. We found that this occurred because the rats given chronic PheB lost more food through the wire cage floor than rats given chronic saline.