The role of ciprofloxacin and trimethoprim-sulfamethoxazole (TMP-SMZ) was evaluated in empiric treatment of uncomplicated Salmonella enteritis in a comparative, double-blind trial. Patients were randomized to receive ciprofloxacin (500 mg), TMP-SMZ (160/800 mg), or placebo orally twice daily for 5 days. There were 65 evaluatable patients with acute, uncomplicated, culture-confirmed Salmonella enteritis. Duration of diarrhea, abdominal pain, or vomiting and time to defervescence were not significantly different for patients treated with ciprofloxacin, TMP-SMZ, or placebo; there also were no significant differences with respect to full resolution of symptoms for ciprofloxacin versus placebo (point estimate, 0.2 days; 95% confidence interval [CI], -0.5 to 0.9 days) or for TMP-SMZ versus placebo (point estimate, 0.2 days; 95% CI, -1.0 to 0.6 days). The rate of clearance of salmonellae from stools was not significantly different among the groups.