Distribution and elimination of cefamandole 2 g iv were studied in 11 morbidity obese patients during a gastric bypass operation and again on the first postoperative day. Serum, subcutaneous adipose tissue, would drainage, and urine were analyzed by high performance liquid chromatography for cefamandole and pharmacokinetic parameters from the intraoperative period were compared to those obtained postoperatively. Total body clearance was significantly greater (p<0.001) postoperatively (297 ml/min) than intraoperatively (254 ml/min). Volume changes were unpredictable but the elimination rate constant tended to increase postoperatively. Renal clearance and percentage of urinary recovery were significantly increased (p<0.01) postoperatively. The patients had a mean (±SD) volume of the central compartment of 10.3 (±2.3) L, volume at steady state of 18.3 (±3.9) L, and elimination rate constant of 1.67 (±0.63) h-1. Tissue concentrations of cefamandole were highest during the first hour after drug administration and were <1 μg/g after 3.5 hours. Mean wound drainage concentrations ranged between 10 and 12 μg/ml during a dosing interval and dropped to 7 μg/ml 12 hours after the last dose. Intraoperative dosing of cefamandole is required to maintain subcutaneous adipose tissue concentrations >1 μg/g during procedures longer than three hours in morbidly obese patients. A postoperative dose of cefamandole 2 g iv q6h will provide sustained and therapeutic concentrations in the wound drainage of morbidity obese patients.