The pharmacokinetic profile of sulfisoxazole was studied and compared in dogs, swine, and humans. The trial was conducted over a 72-hr period after intravenous administration and a 96-hr period after oral administration in dogs and swine. In humans, the trial was conducted over an 8-hr period after oral administration. A two-compartment model system was used to define the pharmacokinetic profile. The mean half-lives for the distribution phase were 4.08, 1.30, and 0.56 hr in dogs, swine, and humans, respectively. For the elimination phase, the mean half-lives were 33.74, 46.39, and 7.40 hr in dogs, swine, and humans, respectively. The mean volume of the central compartment was approximately the same in dogs and swine, 10.6 and 10.5 liters, respectively. Humans had a smaller volume of distribution, 7.7 liters. The steady-state volumes of distribution were 17.2, 30.3, and 16.2 liters in dogs, swine, and humans, respectively. Dogs and swine excreted 42.2 and 30.7%, respectively, of the intravenous dose and 29.4 and 18.3%, respectively, of the oral dose. The bioavailability was 69.8% in dogs and 100.0% in swine. The fraction of drug bound ranged from 30 to 50% in dogs, 40 to 60% in swine, and 25 to 40% in humans.