Objective To observe the therapeutic effect of folic acid and vitamin B12 combined with citalopram for post-stroke depression. Methods Ninety cases of patients with post-stroke depression were divided into two groups(group A and B) (n=45). Both group A and B were given the conventional treatment of ischemic. Group A received citalopram 20mg/d, group B received folic acid 0.4 mg/d and vitamin B12 0.5 mg/d combined with citalopram. Plasma Hcy were measured before treatment and at the end of 12 weeks of treatment, depression of patients were evaluated with Hamilton Depression Scale (HAMD), clinic nerve function defect score(CSS) were assessed for the patients’ neurological function. Results After 12 weeks, Hcy level in group A haven’t significantly changed(P>0.05), while the Hcy level were significantly decreased in group B(P>0.05), the score of HAMD and CSS in group B were significantly lower than those in group A. Conclusions Folic acid and vitamin B12 combined with citalopram can decrease the Hcy level, improve the symptom of depress and promote the neurological function recovery in the treatment of post-stroke depression. It takes effects better than citalopram alone.