To evaluate a more economical regimen for severe shigella dysentery, treatment with single-dose (SD) ampicillin (100 mg/kg) was compared in a randomized trial with results obtained in a conventional five-day (100 mg/kg per 24 hr) multiple-dose (MD) course. Clinical relapse occurred in one of 23 SD children, no SD or MD adults, and none of 18 MD children. Bacteriologic failures were observed in six of 26 adults compared with one of 24 MD adults (P = 0.05). Four of 10 SD children younger than four years of age failed bacteriologically, compared with one MD child. In SD children, lower ampicillin levels were significantly associated with bacteriologic failure and younger age. Resistance of Escherichia coli to ampicillin, although transiently less in SD patients, was equal in MD and SD patients two weeks after therapy. Thus, in highly endemic areas SD ampicillin is clinically effective therapy for ampicillin-sensitive shigellosis in patients older than four years of age. © 1981 by The University of Chicago.