Increasing prevalence of multidrug-resistant (MDR) Salmonella typhi strains in pediatric cases of typhoid fever and chemotherapy restrictions in children, such as fluoroquinolones, require ongoing clinical evaluations of different antibiotic regimens. Previously reported clinical trials with oral cefixime therapy given as a 12-day regimen (20-30 mg/kg divided twice daily) demonstrated both safety and efficacy. An open trial was undertaken to investigate a short course (8-day) regimen of oral cefixime in an Egyptian public fever hospital. Eighty children were initially enrolled with blood culture confirmation in 60 children. Clinical cure was documented in 57 (95 per cent) with three children requiring a change in antibiotic regimen due to therapeutic failure and one child with culture-confirmed relapsed 21 days post-therapy. All S. typhi isolates were sensitive to cefixime as measured by disk diffusion. Cefixime was well-tolerated with only mild side-effects, including nausea/vomiting (8 per cent) and abdominal cramping with loose stools (6 per cent), which may have been secondary to typhoid fever. Cefixime given in a short 8-day course is safe and effective in the management of MDR typhoid fever in children.