Objective Leptin resistance is thought to be a main mechanism of human obesity. Although some studies suggested that leptin resistance could be relevant to the level of leptin receptor and its downstream signaling pathway, there has been little research on leptin receptor regulation. This paper studied the effect of leptin on its receptors. Methods The human hepatocellur carcinoma cell line HepG 2 was incubated in serum-free medium containing 0, 10 -9, 10 -8, 10 -7, 10 -6 M of human leptin respectively for 24 hrs. Then semi-quantitative RT-PCR was used to measure the changes of long (OB-Rb) and short (OB-Ra: OB-R219.1, OB-R219.3) leptin receptors mRNA expressions in HepG2 cells. Results Both OB-Ra and OB-Rb mRNA were expressed in HepG2 cells, which provided a useful model for studies of leptin receptors regulation. Leptin (10 -7-10 -6 M) induced a significant decrease in the OB-Rb mRNA expression, with the maximum effect at 10 -6 M( 0.43± 0.14 vs 1.01± 0.22), when compared with the control (incubation in the absence of leptin). Similarly, the expressions of OB-R219.1 and OB-R219.3, two isoforms of OB-Ra, were also markedly reduced in cells treated with 10 -8-10 -6 M leptin, with the maximum inhibition for OB-R219.1 at 10 -7 M (44% of the control) and for OB-R219.3 at 10 -6 M (49% of the control). Conclusions Leptin can inhibit the expressions of both OB-Ra and OB-Rb mRNA in HepG2 cells, which may be associated with leptin resistance in vivo.