Ondansetron has been shown to be effective in the treatment of early-onset adult alcohol dependence. To date, no studies have been conducted in adolescents with alcohol dependence to assess the feasibility, safety, tolerability, and potential utility of ondansetron treatment. We conducted an 8-week, prospective, open-label study of ondansetron (4 microg/kg b.i.d.) in 12 adolescents who had alcohol dependence. Oral ondansetron was safe and well tolerated in our sample. Adverse events were mild and resolved quickly without intervention. No subjects discontinued due to adverse events. Intent-to-treat analyses showed a significant within-group decrease (improvement) for drinks/drinking day (t=-3.10, df=11, p=0.01), as well as decreases in drinks/day (t=-2.01, df=11, p=0.06) and percentage of days abstinent (t=1.45, df=11, p=0.18). These preliminary data suggest that ondansetron is safe and well tolerated in adolescents with alcohol dependence. Findings of decreased drinking underscore the need for future double-blind, placebo-controlled studies in this adolescent population.