The serotonin transporter (5-HTT) regulates serotonin transmission and modulates behavioral effects of drug of abuse. A polymorphism in the promoter region of the serotonin transporter gene (5-HTTLPR) yielding a short (S) and long (L) allele has been associated with severity of substance abuse. The aims of the study were to investigate whether 5-HTTLPR genotypes differed in their response to treatment in cocaine- and alcohol-abusing patients. Polymerase chain reaction-based genotyping of a 44 base pair insertion/deletion polymorphism was performed in 141 African American cocaine-dependent patients with concurrent alcohol use who were entering a 12-week behaviorally oriented outpatient treatment program. In treatment, end of treatment and 6-month follow-up outcome measures included changes in Addiction Severity Index (ASI) scores, urine drug screens, days in treatment, individual/group sessions, dropout and completion rates. As expected, there was a reduction in substance abuse by the end of treatment and follow-up (F = 5.15, p = 0.000). However, there were no differences in the reduction in cocaine use across the LL, LS and SS genotypes. Interestingly, individuals with the S allele showed greater severity of alcohol use at admission (F = 4.84, p = 0.03), and the SS genotype showed less improvement in alcohol measures than the LL at follow-up (F = 3.68, p = 0.03), after controlling for baseline variables. While we found no association of the 5-HTTLPR variants with severity of cocaine abuse or any cocaine-related outcome measures, the data suggested that the 5-HTTLPR polymorphism may distinguish responders from non-responders to behavioral treatment in terms of alcohol use. Further investigations are required to determine the role of the 5-HTTLPR polymorphism in influencing treatment - outcome among substance abusers.