We previously reported that long-term treatment with some antidepressants at low concentrations upregulates BCL2/adenovirus E1B 19-kDa-interacting protein 3 (BNIP3) mRNA expression in NG108-15 cells without causing cell damage, suggesting that BNIP3 is a candidate of intrinsic depressive disorder-related factor(s). In this study, to clarify the physiologic functions of BNIP3, we investigated whether BNIP3 is actually related to the depressive condition in the brain using learned helplessness (LH) mice, an animal model of depression. Based on the score of escape failure, an index of depression degree, stressed animals were divided into groups with LH and without depressive-like symptoms (i.e., non-depressed phenotype, non-LH). The score of escape failure of the LH group was decreased after 14 d of treatment with imipramine in a dose-dependent manner. BNIP3 mRNA expression was enhanced in both the LH and non-LH groups. Imipramine treatment at 5 and 20 mg/kg/d enhanced BNIP3 mRNA expression only in the LH group but not in non-LH group or non-stressed group. These results raise the possibility that BNIP3 acts as an antistress factor in the brain.