Post-stroke depression (PSD) has a negative impact on rehabilitation following stroke. No satisfactory antidepressant treatment for PSD has yet been developed. The present study examined the effect of milnacipran, a serotonin and norepinephrine reuptake inhibitor, on PSD patients. Eleven PSD patients taking milnacipran in a rehabilitation hospital were compared to age-matched, sex-matched, and severity of depression at admission-matched PSD patients hospitalized during 2001 who did not take any antidepressant as historical control. Severity of depression was measured using self-rating depression scale for depression (SDS) assessed at admission and discharge after 3 months inpatient rehabilitation. Activities of daily living (ADL) and quality of life (QOL) were measured, respectively, by the functional independence measure (FIM) and a self-completed questionnaire for QOL (QUIK) as outcomes of rehabilitation. For the SDS score, the group taking milnacipran showed significant improvement compared to the control group in our study. FIM was improved in both groups. In the end QUIK did not change significantly in either group. We found no major side-effects of milnacipran among the patients. These results suggest that milnacipran is a safe and effective treatment for PSD for inpatients undergoing rehabilitation.