In a prospective randomized open study, ceftriaxone, 50 mg/kg per day, was compared with ampicillin, 100 mg/kg per day, both given for a period of 5 days, for the treatment of 40 children whose mean (±SD) age was 4.5±3.2 years and who had severe dysentery caused by Shigella organisms. Twenty patients were treated with ceftriaxone and 20 with ampicillin. Both drugs were initially given intravenously for a period of 1 to 2 days and were continued intramuscularly, in the case of ceftriaxone, or orally, in the patients receiving ampicillin. All Shigella organisms isolated were susceptible to ceftriaxone; 28% were resistant to ampicillin. The diarrhea persisted for a mean (±SD) period of 2.5±1.0 days in the ceftriaxone-treated patients versus 6.8±6.3 days in the ampicillin-treated patients ( p<0.005). At the end of the 5 days of therapy, stool cultures for Shigella organisms were negative in 12 (60%) of the 20 patients from the ampicillin group and in all the children (100%) from the ceftriaxone group ( p<0.001). Bacteriologic relapses were observed in eight (40%) of the patients treated with ampicillin but in none of the children treated with ceftriaxone ( p<0.001). In instances of clinical or bacteriologic failure in the ampicillin group, retreatment was instituted in most of the cases with ceftriaxone; persistent clearing of the Shigella organisms from the stool was finally achieved after a mean (±SD) period of 11.75±9.4 days after therapy was started, as compared with 1.85±0.6 days in the ceftriaxone-treated patients ( p<0.001). We conclude that in children with severe shigellosis, treatment with ceftriaxone for 5 days is effective and better than use of ampicillin for clinical cure and eradication of the Shigella organisms from the stool.