Although their use has been deemed plausible by previous investigators, the role of antibiotics as primary therapy in active Crohn's ileitis is still unclear. Here we detail the response of four patients with active ileitis to ciprofloxacin, a quinolone antibiotic. Each patient had a dramatic improvement in abdominal pain and diarrhea coincident with the institution of ciprofloxacin, despite the absence of any obvious enteric infection. It is uncertain whether ciprofloxacin is treating an undetected pathogen, bacterial overgrowth, an unsuspected microperforation, or even if it is having its effect through a mechanism entirely unrelated to its antimicrobial properties. Our experience suggests that there is a need for a prospective controlled trial of ciprofloxacin or other antibiotics in active Crohn's ileitis.