The 116C/G polymorphism in the promoter region of XBP1 is known to be associated with bipolar disorders. The G allele of the XBP1-116C/G polymorphism has reduced XBP1-dependent transcription activity compared with the C allele. Valproate treatment has been known to rescue the impaired response of cells with the G allele. We investigated the hypothesis that the G allele of XBP1-116C/G has better prophylactic treatment response to valproate compared to the C allele. This study involved 51 patients with bipolar disorder who were treated with valproate for prophylactic treatment. Prophylactic treatment response to valproate was retrospectively assessed using a scale described by Grof et al. [Grof, P., Duffy, A., Cavazzoni, P., Grof, E., Garnham, J., MacDougall, M., O'Donovan, C., Alda, M., 2002. Is response to prophylactic lithium a familial trait? Journal of Clinical Psychiatry 63, 942-947.]. We found that the patients with the G allele of XBP1-116C/G showed a better prophylactic treatment response to valproate compared to the C allele. This result is in agreement with in-vitro data showing that valproate ameliorates the endoplasmic reticulum (ER)-stress response compromised by the G allele.