The establishment of, and sex differences in, physical dependence on methaqualone (MQ) in rats were studied by the drug-admixed food (DAF) method. Female and male rats were treated with MQ-admixed food on the same schedule of gradually increasing doses (0.5 and 1 to 6 mg of methaqualone/g of food). Only female rats showed hypothermia from MQ at 1 and 2 mg/g and motor incoordination from MQ at 4 and 6 mg/g of food. Moreover, after MQ withdrawal, severe withdrawal signs, including convulsions and death, were observed in female rats, but not in male rats. We also instituted a different schedule of graded increases in dose (1 and 2 to 10 and 12 mg/g of food) to develop physical dependence on MQ in male rats. Under this schedule male rats exhibited a hypothermia and severe motor incoordination from MQ 6 and 8 mg/g of food condition. After MQ withdrawal, various severe signs of MQ withdrawal occurred, including tremor, convulsions and death. These results demonstrate that severe physical dependence on MQ in both sexes can be established using the DAF method, and that there are marked sex differences in the physical dependence on MQ.