Failure of antibiotic prophylaxis to prevent infectious complications following colorectal operations is reported to occur in 5 to 10% of all cases. Factors such as the length of surgery and inadequate antibacterial coverage or duration predispose patients to higher rates of infectious complications. The pharmacokinetics of cefoxitin in eight patients undergoing colectomy, mucosal proctectomy, and endorectal ileal pouch-anal anastomosis (IPAA) for chronic ulcerative colitis or familial polyposis coli were examined. Peak plasma concentrations were 40% higher than values reported in healthy volunteers. During the first dose, the plasma half-life of cefoxitin was similar to plasma half-lives reported in healthy volunteers; however, total body clearance was reduced five- to eightfold. These data suggest that the volume of distribution of cefoxitin was also markedly reduced. Fluid replacement during the operation produced lower cefoxitin peak plasma concentrations after the second dose. Cefoxitin clearance increased during the second dose after fluid replacement, but remained below that reported in healthy volunteers. These data suggest that fluid depletion resulting in decreased kidney perfusion contributed to a reduction in drug clearance. The amount of cefoxitin recovered in the urine during the 12-hour study period averaged 53%. Tissue concentrations of cefoxitin in proximal colon, distal colon, rectal mucosa, and rectal muscle tissue ranged from 0.2 to 9.3 mcg/g of tissue. The preoperative fluid status of the patient, the time of drug administration, and the amount of extra-renal drug elimination appear to be important factors, affecting the disposition of parenterally administered prophylactic antibiotics in patients undergoing colorectal operations.