Objective: Severe drinking can cause serious morbidity and death. Because the serotonin transporter (5-HTT) is an important regulator of neuronal 5-HT function, allelic differences at that gene may modulate the severity of alcohol consumption and predict therapeutic response to the 5-HT3 receptor antagonist, ondansetron. Method: The authors randomized 283 alcoholics by genotype in the 5′-regulatory region of the 5-HTT gene (LL/LS/SS), with additional genotyping for another functional single-nucleotide polymorphism (T/G), rs1042173, in the 3′-untranslated region, in a double-blind controlled trial. Participants received either ondansetron (4 μg/kg twice daily) or placebo for 11 weeks, plus standardized cognitive-behavioral therapy. Results: Individuals with the LL genotype who received ondansetron had a lower mean number of drinks per drinking day (-1.62) and a higher percentage of days abstinent (11.27% ) than those who received placebo. Among ondansetron recipients, the number of drinks per drinking day was lower (-1.53) and the percentage of days abstinent higher (9.73% ) in LL compared with LS/SS individuals. LL individuals in the ondansetron group also had a lower number of drinks per drinking day (-1.45) and a higher percentage of days abstinent (9.65% ) than all other genotype and treatment groups combined. For both number of drinks per drinking day and percentage of days abstinent, 5′-HTTLPR and rs1042173 variants interacted significantly. LL/TT individuals in the ondansetron group had a lower number of drinks per drinking day (-2.63) and a higher percentage of days abstinent (16.99% ) than all other genotype and treatment groups combined. Conclusions: The authors propose a new pharmacogenetic approach using ondansetron to treat severe drinking and improve abstinence in alcoholics.