Abstract: Objective To explore the effects of fluoxetine on the level of serum chemokines in chronic unpredicted mild stress (CUMS) rats. Methods CUMS and single housing were used to induce depressive-like behavior in rats. Depressive-like behavior was evaluated by open-field test, sucrose preference test, body weight and serum corticosterone level. The levels of serum chemokines CCL2, CCL5, CCL11, CXCL10 and CX3CL1 were measured by Luminex assays. Results The content of serum CCL2, CCL5 and CXCL10 obviously increased while CX3CL1 level significantly reduced in CUMS rats, compared with normal healthy rats. There was no significant difference in CCL11. Fluoxetine treatment obviously alleviated the depressive-like behavior and significantly regulated CCL2 and CXCL10. Conclusions Chemokines are related with the development and overcome of depression. Fluoxetine may play its antidepressant role through regulating the expression of chemokines.