Introduction: Ample evidence suggested a role of sigma-1 receptor in affective disorders since the interaction of numerous antidepressants with sigma receptors was discovered. A recent study on Japanese subjects found a genetic variant within the encoding gene SIGMAR1 (rs1800866A>C) associated with major depressive disorder (MDD). We aimed to evaluate the same polymorphism in both MDD and bipolar disorder (BD) as well as its relationship to response to treatment with antidepressants and mood stabilizers. Methods: A total of 238 MDD patients treated for an acute episode of depression, 132 BD patients in treatment with mood stabilizers for a manic or mixed episode, and 324 controls were genotyped for rs1800866. At discharge, response to treatments was evaluated in MDD and BD patients by the Hamilton Rating Scale for Depression (HRSD) and the Young Mania Rating Score (YMRS), respectively. Results: In our Korean sample, allele frequencies were different from those reported in other Asian and non-Asian populations. The CC genotype was associated with BD and, as a trend, with MDD. No significant effect was observed on response to antidepressants in MDD or mood stabilizers in BD, although the CC genotype was more frequent among BD patients experiencing a mixed episode. Conclusion: The present findings are the first to propose the putative role of genetic variants within SIGMAR1 and sigma-1 receptor in BD. Sigma-1 receptor can modulate a number of central neurotransmitter systems as well as some other signaling pathways (e.g., neurotrophin and growth factor signaling) which are seemingly involved in BD and other mood disorders.