Chloramphenicol remains the drug of choice for the treatment of typhoid fever in most areas despite the risks of relapses and toxicity. In a comparison of the efficacy of trimethoprim-sulfamethoxazole (TMP-SMZ) and chloramphenicol against typhoid fever, 60 patients in Indonesia were randomly assigned to receive either TMP-SMZ (320 mg of TMP and 1,600 mg of SMZ daily) or chloramphenicol (2 g daily) for 14 days. TMP-SMZ was significantly more effective in sterilizing the blood, but the two drugs were equally effective with regard to relapse rate, frequency of prolonged fever, and mortality. Use of TMP-SMZ in Vietnam for the treatment of typhoid fever caused by chloramphenicol-resistant Salmonella typhi showed that TMP-SMZ is as effective as ampicillin. Likewise, a review of other published reports suggests that TMP-SMZ has an overall record in the treatment of typhoid fever that is equal to or better than the records of other available drugs. TMP-SMZ has emerged as a satisfactory alternative to chloramphenicol for the treatment of typhoid fever and should be especially useful in areas where chloramphenicol-resistant S. typhi has been isolated.