Leptin, the adipocyte-derived hormone, is secreted into the blood and regulates body weight via its receptors in the hypothalamus. Leptin receptors are also present in many peripheral tissues implicating leptin in the regulation of other body functions, including reproduction, liver and enteric metabolism, hematopoiesis, and immunity. Four splice variants of the leptin receptor have been identified in humans: the long isoform that has full intracellular signaling capacity and 3 shorter isoforms that differ in the length of their cytoplasmic tail. Here, we report the quantification by reverse transcriptase-polymerase chain reaction (RT-PCR) of the relative expression levels of the 2 major leptin receptor splice variants, the long (OB-RL) and the shortest membrane bound variant (OB-RS) in mononuclear cells from peripheral blood of 15 healthy human subjects (9 women and 6 men), with a body mass index (BMI) that ranged from 19.7 to 41.6. Both OB-RL and OB-RS were coexpressed in all mRNAs tested. However, the expression of the short form (OB-RS), was on average 8-fold higher than the expression of the long form (OB-RL) (120.8 +/- 12.9 v 14.6 +/- 3.0 relative intensity units, P < .001). The predominance of the short splice variant over the long one was apparent in all samples and ranged from 4- to 27-fold. There was no significant difference in the expression of either isoform between men and women. However, the relative expression of both OB-RS and OB-RL isoforms was significantly lower in the overweight (BMI > 26), compared with the lean subjects (BMI < 25) (78.8 +/- 9.1 and 6.2 +/- 1.1 v148.8 +/- 14.4 and 18.9 +/- 4.0 relative intensity units, respectively, P < .03) and was inversely correlated with the BMI and plasma leptin levels (P < .01). In conclusion, the expression of OB-RS and OB-RL leptin receptor isoforms appears to be reduced in human peripheral blood mononuclear cells from obese individuals, with OB-RS remaining the predominant leptin receptor isoform. This might have implications for the bioavailability and/or action of circulating leptin not only on these cells, but also on other target tissues.