We present two cases of treatment-resistant depression that improved with recognition and correction of the underlying medical etiology of vitamin B12 deficiency. Supplementations of vitamin B12 to the same antidepressant regimen that the patient had not responded earlier led to response. Two male subjects who were vegetarians presented with long-standing histories of depression and had not responded to three adequate trials of antidepressants. Upon investigation, the authors found that the subjects had low vitamin B12 levels. Both cases improved with supplementation of vitamin B12. Subjects with depression who do not respond to conventional antidepressants should be evaluated for nutritional factors.