Antimicrobial-resistant typhoid fever in Saigon was studied by examining in vitro antimicrobial susceptibilities of Salmonella typhi strains and conducting a randomized clinical trial of ampicillin and trimethoprim-sulfamethoxazole (TMP-SMZ). Isolates of S. typhi were obtained from blood or stool cultures of 90 patients. Of 87 isolates tested for antimicrobial susceptibility, 65 (75%) were resistant (R) to chloramphenicol, streptomycin, sulfonamide, and tetracycline, and 22 (25%) were susceptible (S). The drug resistance was transferable to Escherichia coli and was found in 11 different Vi-phage types. All isolates were susceptible to ampicillin and to TMP-SMZ. Agar dilution studies of TMP and SMZ showed synergistic inhibition of growth in all 18 S isolates and in 12 of 48 R isolates tested. The clinical trial of ampicillin and TMP-SMZ showed that both drugs were equally effective. Treatment failure with both drugs was more frequent in patients with S isolates than in patients with R isolates. Therefore, in an area where antimicrobial-resistant typhoid fever exists, patients with R isolates should receive either ampicillin or TMP-SMZ, but patients with S isolates should be treated with chloramphenicol.