Late-onset/low-vulnerability alcoholics (LOAs) appear to drink less when treated with a selective serotonin reuptake inhibitor than placebo, whereas early-onset/high-vulnerability alcoholics (EOAs) show the opposite effect. We conducted a 12-week, parallel-group, placebo-controlled trial of the efficacy of sertraline in alcohol dependence (AD). We compared the effects in LOAs versus EOAs and examined the moderating effects of a functional polymorphism in the serotonin transporter gene. Patients (N = 134, 80.6% male, 34.3% EOAs) with Diagnostic and Statistical Manual of Mental Disorders-IV AD received up to 200 mg of sertraline (n = 63) or placebo (n = 71) daily. We used urn randomization, and patients were genotyped for the tri-allelic 5-hydroxytryptamine transporter protein linked promoter region polymorphism. Planned analyses included main and interaction effects of medication group, age of onset (≤ 25 years vs >25 years), and genotype (L'/L' vs S' carriers) on drinking outcomes. Results showed that the moderating effect of age of onset on the response to sertraline was conditional on genotype. There were no main or interaction effects among S' allele carriers. However, in L' homozygotes, the effects of medication group varied by age of onset (P = 0.002). At the end of treatment, LOAs reported fewer drinking and heavy drinking days when treated with sertraline (P = 0.011), whereas EOAs had fewer drinking and heavy drinking days when treated with placebo (P < 0.001). The small cell sizes and high rate of attrition, particularly for L' homozygotes, render these findings preliminary and their replication in larger samples necessary. Because AD is common, particularly in medical settings, and selective serotonin reuptake inhibitors are widely prescribed by practitioners, these findings have potential public health significance and warrant further evaluation.