The efficacy of orally administered trimethoprim sulfamethoxazole was compared with that of oral amoxicillin in therapy of typhoid fever due to both epidemic chloramphenicol resistant and endemic chloramphenicol sensitive Salmonella typhi. Both drug regimens were effective and of comparable value in treatment of chloramphenicol resistant infections, as measured by duration of fever (124 hr and 115 hr, respectively) and duration of bacteremia (1.0 and 0.4 days, respectively). Trimethoprim sulfamethoxazole therapy of infections due to chloramphenicol sensitive S. typhi resulted in more rapid lysis of fever than did amoxicillin therapy. Trimethoprim and sulfamethoxazole were not synergistic in vitro against the chloramphenicol resistant strain of S. typhi, and the role of sulfamethoxazole in treatment of such infections appears to be minimal. Oral administration of trimethoprim sulfamethoxazole is effective therapy of chloramphenicol resistant, and probably of ampicillin amoxicillin resistant, typhoid fever.