We evaluated the response to therapy in a series of 876 children consecutively admitted to The Aga Khan University Hospital with culture-proven typhoid, including 281 cases infected with multi-drug-resistant (MDR) strains. Among sensitive isolates there was no significant difference in cure rates, failure rates and time to defervescence with either ampicillin or chloramphenicol. Of the 217 children with MDR typhoid who received therapy with third-generation cephalosporins, the outcome was significantly better with intravenous ceftriaxone compared with cefotaxime. Despite comparable cure rates, the time to defervescence was significantly longer among MDR strains treated with ceftriaxone versus sensitive strains (mean (SD): 7.2 (3.4) versus 6.3 (29) days; p < 0.05). Earlier recognition and introduction of appropriate second-line therapy has allowed us to reduce the case fatality rates of typhoid to under 1%. Although a 14-day course of ceftriaxone can be used successfully to treat most children hospitalized with MDR typhoid, there is a need to evaluate the role of short-course therapy or alternative therapeutic agents.