The antiobesity effects of leptin are mediated by the obese receptor (OB-R), a member of the cytokine receptor superfamily. Several isoforms of OB-R that differ in the length of the cytoplasmic domain have been described. An isoform with a long cytoplasmic domain of 302 amino acids, termed OB-Rb, contains the conserved box 1 and box 2 motifs and is likely to be responsible for leptin-induced signaling. A point mutation in the OB-R gene of diabetes (db) mice generates a new splice donor that interferes with the correct splicing of the OB-Rb mRNA and is predicted to cause absence of the OB-Rb protein in db/db mice. Here we examined the signaling potential of the long isoform, OB-Rb, and of a short isoform, OB-Ra, in BaF3 cells, a factor-dependent hematopoietic cell line. The long isoform was able to generate a proliferative signal and upon leptin binding, activated janus kinase 2 (Jak2). Consistently, antibodies directed against the extracellular domain of OB-R coprecipitated Jak2. The short isoform, OB-Ra, was inactive in both proliferation and Jak activation. These results provide further support for the long isoform, OB-Rb, being the principal mediator of the effects of leptin and help to explain why db/db mice are resistant to leptin, despite the presence of the short OB-R isoforms.