Objective: To explore the combination effect of trazodone and fluoxetine in the treatment of post stroke depression with insomnia. Methods: Sixty-two patients with post-stroke depression were randomly divided into a control group (n=32) and a treatment group (n=30). The control group was treated with fluoxetine; the treatment group was treated with the combination of trazodone and fluoxetine dispersible tablets. The patients were treated for 12 weeks and followed-up for 6 to 12 months. Clinical symptoms, adverse reactions were recorded. The Self-Depression Scale (SDS), Pittsburgh Sleep Quality Index (PSQI), Hamilton Depression Scale (HAMD) and Activity of Daily Life Scale (ADL) were used. Results: The effective rate was significantly different between the two groups (87% in the treatment group, 73% in the control group, χ2=4.565, P<0.05). During the follow-up, 2 cases repeated in the treatment group, and 10 cases in the control group, the difference was statistically significant (χ2=5.163, P<0.05). After the 12-week treatment, the decrease of SDS, PQSI, HAMD scale, and increase of ADL in the treatment group were significantly higher than those of the control group. Conclusion: Trazodone combined with fluoxetine can significantly improve the clinical symptoms of patients with post stroke depression with insomnia, with less adverse reactions, lower recurrence rate.