Twenty-one obese (14 women; 7 men) and 21 normal (11 women; 10 men) drug-free and age-matched subjects were given single 650-mg IV doses of acetaminophen. Mean total body weights (TBW) for the groups were as follows: obese men, 134.9 kg; control men 70.6 kg; obese women, 87.9 kg; and control women, 55.0 kg; ideal body weight (IBW) was similar for all of the groups. Acetaminophen elimination half-life (t1/2 beta) did not differ among groups. Absolute volume of distribution (Vd) was greater in obese than in control men (109 and 77 l, P less than 0.05) and greater in control men than in control women (77 and 52 l, P less than 0.05), but Vd corrected for TBW was smaller in obese than in control men (0.81 and 1.09 l/kg TBW, P less than 0.05) and smaller in obese than control women (0.71 and 0.95 l/kg TBW, P less than 0.05). Absolute metabolic clearance was greater in obese than in control men (484 and 323 ml/min, P less than 0.05), in obese than in control women (312 and 227 ml/min, P less than 0.05), and in control men than women (323 and 227 ml/min, P less than 0.05). After correction for TBW, however, clearance between control and obese subjects of the same sex did not differ. Acetaminophen Vd is increased in obesity and in men relative to women, but the drug's distribution into body weight exceeding IBW is less extensive than that into IBW. For men the distribution ratio is 0.44 and for women, 0.31. Acetaminophen clearance increases with body weight and therefore is much greater in obese patients and in men.