The efficacy and toxicity of ciprofloxacin, an orally administered fluoroquinolone, were evaluated in 24 infections in 23 patients with osteomyelitis caused by aerobic gram-negative bacilli. The diagnosis was confirmed by surgical findings and the results of bone biopsy and culture of bone or deep soft tissue. The aerobic gram-negative bacilli were Pseudomonas aeruginosa (15 isolates), Serratia marcescens (five isolates), Escherichia coli (three isolates), Enterobacter species (three isolates), Proteus mirabilis (one isolate), Pseudomonas fluorescens (one isolate), and Klebsiella pneumoniae (one isolate). Minimal bactericidal concentrations (MBCs) were 1.56 micrograms/ml or less for all but one isolate. Nine infections were polymicrobial, involving aerobic gram-positive cocci or anaerobes in addition to aerobic gram-negative bacilli. Additional antibiotics to which the aerobic gram-negative bacilli were resistant were given when the additional organisms were resistant to ciprofloxacin. Patients received 750 mg of ciprofloxacin twice daily for a mean of 62 days. Peak serum levels of ciprofloxacin were at least threefold higher than the MBCs in 20 of 24 patients. Twenty of 22 infections in which a full course of therapy was completed were without evidence of active disease at one to 17 months posttreatment. A sternotomy wound infection relapsed after eight weeks of therapy with a newly resistant S. marcescens strain, and an infection of a compound fracture relapsed two months posttreatment with a still sensitive P. aeruginosa strain. Toxicity was minimal in most patients: eosinophilia (six patients), nausea (eight patients), mild elevation in transaminase levels (three patients), pruritus (one patient), diarrhea (two patients), thrush (two patients), rash (two patients), and mild leukopenia (one patient). Two additional patients had severe side effects (vertigo in one and acute renal failure in another) that required discontinuation of ciprofloxacin therapy. Overall, ciprofloxacin is a promising agent for the oral treatment of gram-negative bacillary osteomyelitis.