Depressive disorders are frequently managed with long-term use of antidepressant medication. Fluoxetine (FLX) is the first selective serotonin reuptake inhibitor to be widely available for the treatment of depression. The present study focuses on the effects and mechanisms of the lipid metabolism abnormalities caused by FLX in patients and in a mouse model of depression. Depression severity was assessed by the Hamilton Depression Scale (HAMD). Triglyceride (TG), cholesterol (TC) and low-density lipoprotein (LDL) serum levels were assessed in 28 patients with depression, aged 31.2±3.3 years, treated with FLX (20 to 60 mg/day) for 8 weeks. Meanwhile, the serum levels of other lipid metabolism-related parameters, such as high-density lipoprotein (HDL), apolipoprotein Al (APOA1) and apolipoprotein B (ApoB), were also determined. The influence of FLX on the hepatic lipid profile and hepatic gene expression of both lipogenic and lipolytic enzymes was evaluated in a mouse model of depression treated with FLX (10 mg·kg-1-d-1, ip) for 4 weeks. We showed that the serum TG, TC and LDL levels were significantly increased in patients with depression after FLX treatment. The elevation in serum TG levels in the patients was not affected by gender or family history. FLX treatment did not significantly alter serum HDL, APOA1 or APOB levels in the patients. We further demonstrated in mice with depression that FLX treatment increased the hepatic TG level by increasing the expression of lipogenic enzymes and decreasing the expression of lipolytic enzymes in the liver. Antidepressive therapy with FLX is associated with lipid metabolism abnormalities, which are in part mediated by disturbances in hepatic lipid metabolism homeostasis. The findings contribute to the uncovering of metabolic adverse reactions in the pharmacological therapy of depression.