Twenty-two unrelated healthy subjects and 28 unrelated patients with insulin-dependent diabetes were given 200 mg of caffeine and 10 mg of debrisoquin on two occasions. In healthy subjects, caffeine and debrisoquin metabolism and the oxidation and acetylation phenotypes were stable. In the patients with diabetes, the two tests showed a significant decrease in the glycosylated hemoglobin level and a significant increase in the 24-hour elimination rate of all caffeine metabolites. Most of the values were lower compared with those of healthy subjects during the first test. Because of these variations, caffeine cannot be used to determine the rapid or slow acetylator status in patients with diabetes. In contrast, neither the oxidation of debrisoquin nor the phenotypic expression was disturbed. These results reiterate the need for defining the administration conditions and surveying the drugs used in the treatment of diabetes mellitus complications.