Bacterial pneumonia in horses is frequently caused by gram-positive bacteria, and as such, empirical therapy should include antimicrobial agents with activity against this class of pathogen. However, gram-negative pathogens may coexist, which would make broad-spectrum antimicrobial coverage necessary. Because of potential drug-associated risks (e.g., nephrotoxicity in dehydrated patients, peracute colitis in racehorses), some antimicrobial agents may not be appropriate for empirical use. Enrofloxacin offers an enhanced spectrum of antimicrobial activity with reduced risk of complication. This study investigated increasing doses of enrofloxacin (1.25, 2.5, 5.0, and 7.5 mg/kg) in the treatment of a model of transport-associated respiratory disease. Findings suggest that solo therapy with enrofloxacin may not be appropriate for the treatment of gram-positive pathogens in association with this transport model of equine respiratory disease.