Effects of fasting on the metabolsim and distribution of antipyrine and tolbutamide were studied in 13 obese, but otherwise healthy, volunteers. Only 6 of the 13 subjects decreased their metabolic clearance rate (MCR) during fasting; no significant change occurred during fasting in the mean MCR of either drug. These results are in contrast with reported changed rates of drug metabolism in fasting experimental animals. The apparent volume of distribution (aVd) of antipyrine decreased during fasting in each of 7 subjects receiving oral test doses of antipyrine; the mean control value plus or minus standard deviation was 61 plus or minus 16 1, whereas during fasting the mean became 52 plus or minus 17 1. The aVd plus or minus SD of tolbutamide decreased in 4 of the 6 volunteers receiving intravenous test doses of tolbutamide; the mean control value in these6 volunteers was 8.3 plus or minus 1.7 1; during fasting it was 7.4 plus or minus 1.91.