Of 28 strains of Salmonella typhosa collected in late 1972 in Vietnam, 4 had minimum inhibitory concentrations to chloramphenicol of >100 mug/ml. Median minimum inhibitory concentrations of all strains to oxolinic acid were 0.39 mug/ml; ampicillin, 6.25 mug/ml; amoxicillin, 0.39 mug/ml. Widespread typhoid fever appeared in mid-1973 with more than three-fourths of strains found to be resistant to chloramphenicol. Peak serum concentrations of oxolinic acid average 3.0 mug/ml after the oral ingestion of 1.0 g. In July 1974, a pilot study was begun to evaluate the efficacy of oxolinic acid in vivo, recognizing the discrepancy between in vitro and in vivo results with many agents evaluated in the treatment of typhoid fever. Seven patients with typhoid fever, six with positive blood cultures, were treated with oxolinic acid (1.5 g twice daily by mouth, a daily dose that averaged 75 mg/kg per day) for 5 to 12 days. In four of six patients, blood cultures became negative at 2 to 3 days, with another being negative at 6 days. Despite negative blood cultures, all but one patient remained clinically ill with temperatures of >39.5 C at 4 to 9 days. All strains were susceptible to 0.19 mug of oxolinic acid per ml, and resistant strains did not occur. One patient died after being changed to ampicillin, one left against advice, three responded to amoxicillin, and one died with pseudomonas bacteremia. Toxicity to oxolinic acid did not occur.