Context: Early-onset alcoholism differs from late-onset alcoholism by its association with greater serotonergic abnormality and antisocial behaviors. Thus, individuals with early-onset alcoholism may be responsive to treatment with a selective serotonergic agent. Objective: To test the hypothesis that drinking outcomes associated with early vs late-onset alcoholism are differentially improved by the selective 5-HT3 (serotonin) antagonist ondansetron. Design: Double-blind, randomized, placebo-controlled clinical trial. Settings. University of Texas Health Science Center in Houston (April 1995-June 1998) and University of Texas Health Science Center in San Antonio (July 1998-December 1999). Participants. A total of 321 patients with diagnosed alcoholism (mean age, 40.6 years; 70.5% male; 78.6% white) were enrolled, 271 of whom proceeded to randomization. Interventions. After 1 lead-in week of single-blind placebo, patients were randomly assigned to receive 11 weeks of treatment with ondansetron, 1 μg/kg (n =67), 4 μg/kg (n=77), or 16 μg/kg (n =71) twice per day; or identical placebo (n =56). All patients also participated in weekly standardized group cognitive behavioral therapy. Main Outcome Measures: Self-reported alcohol consumption (drinks per day, drinks per drinking day, percentage of days abstinent, and total days abstinent per study week); and plasma carbohydrate deficient transferrin (CDT) level, an objective and sensitive marker of transient alcohol consumption. Results: Patients with early-onset alcoholism who received ondansetron (1, 4, and 16 μg/kg twice per day) compared with those who were administered placebo, had fewer drinks per day (1.89, 1.56, and 1.87 vs 3.30; P=.03, P=.01, and P=.02, respectively) and drinks per drinking day (4.75, 4.28, and 5.18 vs 6.90; P=.03, P=.004, and P=.03, respectively). Ondansetron, 4 μg/kg twice per day, was superior to placebo in increasing percentage of days abstinent (70.10 vs 50.20; P=.02)and total days abstinent per study week (6.74 vs 5.92; P=.03). Among patients with early-onset alcoholism, there was a significant difference in the mean log CDT ratio between those who received ondansetron (1 and 4 μg/kg twice per day) compared with those who received the placebo (-0.17 and -0.19 vs 0.12; P=.03 and P=.01, respectively). Conclusion: Our results suggest that ondansetron (particularly the 4 μg/kg twice per day dosage) is an effective treatment for patients with early-onset alcoholism, presumably by ameliorating an underlying serotonergic abnormality.