Sex differences in physical dependence on barbital (BAR), which is not readily metabolized in rats, were studied by the drug-admixed food method. The concentration of BAR in the food was gradually increased from 1 and 2 up to 6 and 8 mg/g food concurrently available to each rat over a period of 36 days in both male and female Sprague-Dawley rats. Sedation and muscle relaxation were observed in males at the 4 and 6 mg/g condition and to a greater degree at 6 and 8 mg/g of food. This effect was seen only at the highest drug concentration, 6 and 8 mg/g food, in females. Physical dependence was assessed in both sexes after substitution of normal food for the BAR-admixed food. Various signs of BAR withdrawal were observed including vocalization, irritability, muscle rigidity, tremors and convulsions. The incidence of convulsions was 76.9% in females and 45.5% in males, respectively. Maximum weight loss was 15.4% in females and 12.1% in males. However, brain BAR concentrations in the male rats were higher than that in the female rats 9 hours before onset of withdrawal and at all later time points tested. Thus, we have demonstrated that weak sex differences in physical dependence on BAR exist and suggest that this difference resulted from a difference in CNS sensitivity to BAR.