BACKGROUND: Systemic antibiotics are routinely prescribed for severe acute malnutrition (SAM). However, there is no consensus regarding the most suitable regimen. In a therapeutic feeding centre in Khartoum, Sudan, a randomised, unblinded, superiority-controlled trial was conducted, comparing once daily intramuscular injection with ceftriaxone for 2 days with oral amoxicillin twice daily for 5 days in children aged 6-59 months with SAM. METHODS: Commencing with the first measured weight gain (WG) following admission, the risk difference and 95% confidence interval (95% CI) for children with a WG > or = 10 g/kg/day were calculated over a 14-day period. The recovery rate and case fatality ratio (CFR) between the two groups were also calculated. RESULTS: In an intention-to-treat analysis of 458 children, 53.5% (123/230) in the amoxicillin group and 55.7% (127/228, difference 2.2%, 95% CI -6.9-11.3) in the ceftriaxone group had a WG > or = 10 g/kg/day during a 14-day period. Recovery rate was 70% (161/230) in the amoxicillin group and 74.6% (170/228) in the ceftriaxone group (p=0.27). CFR was 3.9% (9/230) and 3.1% (7/228), respectively (p=0.67). Most deaths occurred within the 1st 2 weeks of admission. CONCLUSION: In the absence of severe complications, either ceftriaxone or amoxicillin is appropriate for malnourished children. However, in ambulatory programmes, especially where there are large numbers of admissions, ceftriaxone should facilitate the work of medical personnel.