Ciliary neurotrophic factor (CNTF) analogues were reported to ameliorate fatty liver in db/db or high‐fat diet‐fed mice. It is generally thought that CNTF exerts its actions centrally. The aim of this study was to investigate whether peripheral effects of CNTF analogues are involved in the therapeutic effect on high fat‐induced hepatic steatosis. The rat model of fatty liver was induced by a high‐fat diet (HFD) for 12 weeks. In the next 2 weeks, rats were fed the HFD along with subcutaneous injection of vehicle or mutant recombinant human CNTF (rhmCNTF 0.05‐0.2 mg/kg per day). Steatotic HepG2 cells were induced by 50% fetal bovine serum (FBS) for 48 hours, and then treated with rhmCNTF for 24 hours. The results showed that after rhmCNTF treatment, hepatic triglyceride (TG) accumulation was attenuated both in vivo and in vitro. RhmCNTF increased protein expression of CPT‐1 and PPARα, and decreased SREBP‐1c, FAS and SCD‐1 in steatotic HepG2 cells. But the production of nitric oxide and 8‐isoPGF2α in steatotic HepG2 cells was not affected by rhmCNTF. These results suggest that rhmCNTF has a peripheral effect that alleviates fat‐induced hepatic steatosis.