Ciprofloxacin, 500 mg every 12 h, was compared with ampicillin, 500 mg every 6 h, both given for 5 days, in the treatment of 121 adult males hospitalized with severe shigellosis. Treatment was randomized and double-blinded. At the completion of treatment, there was resolution or marked improvement in symptoms in 57 (95%) of 60 ciprofloxacin-treated patients, 23 (88%) of 26 ampicillin-treated patients infected with an ampicillin-susceptible strain of Shigella, and 15 (43%) of 35 ampicillin-treated patients infected with an ampicillin-resistant strain of Shigella (ampicillin-R group) (P less than .01, ciprofloxacin or ampicillin groups vs. ampicillin-R group). Bacteriologic failure was less common (P less than .025) in the ciprofloxacin group (0/60) than in the ampicillin (3/26, 12%) or ampicillin-R groups (5/35, 14%). Ciprofloxacin-treated patients had a mean of 29 stools during the study, compared with 46 for ampicillin-treated patients (P = .004). Thus ciprofloxacin seems to be an effective, and perhaps superior, alternative to ampicillin in treating patients with shigellosis.