Objective: To evaluate the pharmacokinetics of enrofloxacin and its metabolite ciprofloxacin after administrations of enrofloxacin in sheep. Design: Crossover study performed by IV and IM administrations of 2.5 mg of enrofloxacin/kg of body weight to 2 groups of 3 sheep. After a 15-day resting period, the drug administration was repeated, using the alternative route. Animals: 6 clinically normal Massese sheep of either sex. Procedure: Blood samples were collected at suitable intervals over a 24-hour period, and plasma concentrations of enrofloxacin and its main metabolite ciprofloxacin were determined by a high-performance liquid chromatography method. Pharmacokinetic variables for both substances after IV and IM enrofloxacin administrations were calculated by use of statistical moments and were analyzed, using a crossover ANOVA. Results: After IV administration of enrofloxacin, a rapid distribution phase was followed by a slower elimination phase. When the same dose was administered IM, enrofloxacin was rapidly and almost completely absorbed, with bioavailability of 85%. After 24 hours, the mean plasma concentration of ciprofloxacin was similar to that of the parent drug. Conclusions: The large volume of distribution indicates that enrofloxacin is widely distributed in the body of sheep. The fraction of enrofloxacin metabolized to ciprofloxacin (35 and 55% for IV and IM administrations, respectively) suggests that, in this species, the antimicrobial activity of enrofloxacin could be attributable, at least in part, to its mam metabolite ciprofloxacin. Clinical Relevance: IV or IM administration of 2.5 mg of enrofloxacin/kg provides plasma concentrations higher than mean inhibitory concentration for most pathogens in sheep. (Am J Vet Res 1996;57:1040–1043)