This study was carried out to verify the relationship between major depression and cytotoxic T lymphocyte antigen-4 (CTLA-4), which is related to immunological function such as T-cell regulation. Among the Korean patients diagnosed with major depression according to DSM-IV, 77 patients without neurological illness, hormonal disorder, or comorbid mental illness were selected. The stored data on 149 normal Koreans from the Catholic Hemopoietic Stem Cell Bank of Korea, were used as a control group. The data of the Korean control group were compared with those of the studies of different ethnic groups. DNA was extracted from whole blood using proteinase K and the exon 1 region of CTLA-4 gene was amplified by polymerase chain reaction. Gene typing was performed using single strand conformation polymorphism. The results were assessed. There were significant differences in frequencies of CTLA-4 allele (chi2 = 56.472, d.f. = 1, P = 0.001) and genotype (chi2 = 46.132, d.f. = 2, P = 0.001) between the Korean population and the Caucasian population. However, we could not find any differences between the Korean and the Japanese population. There were no significant differences in genotype frequencies of CTLA-4*G/G, CTLA-4*G/A, and CTLA-4*A/A between the patients with major depression and the control group in the Korean population (48.1% vs. 46.3%, 41.6% vs 39.6%, 10.3% vs. 14.1%, respectively). There were no significant differences in allelic frequencies of CTLA-4*G and CTLA-4*A between the patients with major depression and the control group in the Korean population (68.8% vs. 66.1%, 31.2% vs. 33.9%, respectively). Although the present study produced negative results for the association of exon 1 polymorphism of CTLA-4 gene with major depression in the Korean population, further systematic research, including diverse clinical variables, would be necessary.