Medications that act on the serotonergic system have been found to be of benefit in the treatment of alcohol-dependent individuals. In a randomized, placebo-controlled study, the efficacy of 6 weeks of ondansetron, a 5-HT3 antagonist (0.25 mg bid or 2.0 mg bid), in the treatment of 71 nonseverely alcohol-dependent males was tested. The results showed reduction of drinking differences were steadily increasing toward the end of the treatment period approached significance at week 7 in the 0.25 mg group (p= 0.06). Twice as many patients in this group showed >2 standard deviations decrease in drinking compared with the other groups. When patients drinking >10 drinks/drinking day at baseline (n= 11) were excluded from the analysis, significant group differences were found at both treatment and follow-up, with the lower ondansetron dose producing the greatest reduction from baseline (i.e., 2.8 standard drinks; –35% compared with baseline and –21% compared with placebo; p < 0.02–0.001). Within this group, there was an almost 4-fold greater number of patients showing a clinically meaningful decrease in drinking. Lower baseline drinking and higher level of education were significant and strong predictors of drinking reduction during treatment. Ondansetron was very well tolerated; hence, further long-term studies with 5-HT3 antagonists alone or in combination with other treatment components may offer promise for treatment of alcoholism.