OBJECTIVE To determine plasma drug concentrations after IV administration of a bolus followed by continuous rate infusion (CRI) of sodium benzylpenicillin and ceftiofur sodium to healthy adult horses. ANIMALS 6 Thoroughbred mares (3 to 9 years old; mean ± SD body weight, 544 ± 55 kg) with no history of recent antimicrobial treatment. PROCEDURES Horses were used in 2 experiments conducted 14 days apart. For each experiment, horses were housed individually in stables, and catheters were placed bilaterally in both jugular veins for drug administration by CRI (left catheter) and for intermittent collection of blood samples (right catheter). Synovial fluid samples were obtained from carpal joints following ceftiofur administration to evaluate drug diffusion into articular spaces. RESULTS Plasma concentrations above accepted minimum inhibitory concentrations for common pathogens of horses were achieved within 1 minute after bolus administration and remained above the minimum inhibitory concentration for 48 (ceftiofur) or 12 (benzylpenicillin) hours (ie, the duration of the CRI). Mean synovial fluid ceftiofur free acid equivalent concentrations were approximately 46% (range, 25.4% to 59.8%) of plasma concentrations at the end of infusion. CONCLUSIONS AND CLINICAL RELEVANCE Compared with intermittent bolus administration, the loading dose and CRI used less drug but maintained high plasma concentrations for the duration of infusion. By use of pharmacological parameters derived in this study, a loading dose of 2.5 mg/kg and CRI of 200 μg/kg/h should achieve plasma ceftiofur concentrations of 4 μg/mL; a loading dose and CRI of 1.3 mg/kg and 2.5 μg/kg/h, respectively, should achieve plasma benzylpenicillin concentrations of 2 μg/mL.