Disturbances in serotonergic neurotransmission system have been implicated in the etiology of mood disorders. As the importance of genetic factors is well established, genes encoding for proteins of the serotonergic pathway are important candidates to unravel the underlying genetic contribution. We examined two polymorphisms in the serotonin-2A-receptor gene (5-HT2A; T102C and His452Tyr) and the insertion/deletion polymorphism in the promoter region of the serotonin transporter (5-HTTLPR) in a sample of 173 patients with major depression and 121 healthy controls. No statistical significant differences between patients and controls were found for any of the three investigated polymorphisms, neither in the distribution of the genotypes nor in allele frequencies. However, concerning the 5-HTTLPR polymorphism, the frequency of S/S (short allele) homozygotes was higher (23.1%) than in the control group (14.0%), but this failed to reach significance. Moreover we observed a different treatment response in patients with one or two C-alleles of the T102C polymorphism, with a significantly higher decrease in HAMD-17 (ANOVA: d.f. = 1, F = 5,288, P = 0.023) after 4 weeks of antidepressant treatment. Overall our results suggest that the investigated 5-HT2A and 5-HTTLPR polymorphisms are not major susceptibility factors in the etiology of major depression. However, subtypes might be identified at least on a basis of differential treatment response.