We investigated the relationships between LS promoter (SERTPR) and ls intron2 (SERTin2) genetic variants of serotonin transporter (SERT) polymorphisms with treatment response in 130 patients with major depressive disorder (MDD) treated with paroxetine (20 mg/day) for 6 weeks. To assess and evaluate therapeutic response to paroxetine all patients were rated weekly using the HAMD-17 scale. Responders were defined as those subjects with a decrease in HAMD scale by > or = 50% at week 6 of treatment. Comparison of genotypes and alleles frequency of the SERTPR between responders and nonresponders revealed significant differences among genotypes and overrepresentation of the S allele in the group of non-responders (P = 0.0004). SERTin2-ss genotype bearing subjects showed better treatment response compared to ls and ll genotype from the fourth week of treatment (P = 0.035). Statistical differences were also found in distributions of the estimated haplotypes between responders and non-responders, while subsequent analysis revealed overrepresentation of S/l haplotype (P = 0.006) in the group of non-responders. SERTPR and SERTin2 were found to be in linkage disequilibrium in studied population. These findings identify genetic factors associated with paroxetine treatment response in MDD patients.