Two Quarter Horse racehorses presented to a referral hospital for acute diarrhea after an eight day course of doxycycline. Both horses were treated presumptively for antimicrobial-induced colitis and recovered without complications such as severe endotoxemia or laminitis. Presented here is a case report and review of antimicrobial-induced colitis in the adult horse, with emphasis on appropriate testing and mechanism of Clostridium difficile colitis.