Being overweight is a risk factor for postmenopausal breast cancer and is associated with an increased incidence and shortened latency of spontaneous and chemically induced mammary tumors in rodents. However, leptin-deficient obese LepobLepob female mice have reduced incidences of spontaneous and oncogene-induced mammary tumors. Of interest, leptin enhances the proliferation of human breast cancer cell lines in which leptin receptors are expressed, which suggests that leptin signaling plays a role in tumor development. We evaluated oncogene-induced mammary tumor development in obese MMTV-TGF-α/LeprdbLeprdb mice that exhibit a defect in OB-Rb, which is considered to be the major signaling isoform of the leptin receptor. Lepr and MMTV-TGF-α mice were crossed, and the offspring were genotyped for oncogene expression and the determination of Lepr status. Lean MMTV-TGF-α/Lepr+Lepr+ (homozygous) and MMTV-TGF-α/Lepr+Leprdb (heterozygous) mice and obese MMTV-TGF-α/LeprdbLeprdb mice were monitored until age 104 weeks. Body weights of MMTV-TGF-α/ Lepr dbLeprdb mice were significantly heavier than those of the lean groups. No mammary tumors were detected in MMTV-TGF-α/Lepr dbLeprdb mice, whereas the incidence of mammary tumors in MMTV-TGF-α/Lepr+Lepr+ and MMTV-TGF-α/ Lepr+Lepdb mice was 69% and 82%, respectively. Examination of mammary tissue whole mounts indicated an absence of duct formation and branching for MMTV-TGF-α/LeprdbLeprdb mice. Both age at mammary tumor detection and tumor burden (tumors/mouse and tumor weights) were similar for the lean genotypes. Serum leptin levels of MMTV-TGF-α/LeprdbLeprdb mice were 12-20-fold higher than levels of lean mice. Thus, despite elevated serum leptin levels, leptin receptor-deficient MMTV-TGF-α/LeprdbLeprdb mice do not develop mammary tumors. This study provides additional evidence that leptin and its cognate receptor may be involved in mammary tumorigenesis.