This prospective study aimed to investigate the impact of letrozole treatment on the lipid profile of postmenopausal early breast cancer patients. Sixty postmenopausal women diagnosed with hormone receptor-positive early breast cancer were enrolled in this study. Lipid profile parameters, including TC, LDL-C, HDL-C, and TG, were measured at baseline and at regular intervals during a one-year treatment period with letrozole (2.5 mg/day). Patients' medical history, including previous treatment with tamoxifen, chemotherapy or radiotherapy, was also recorded. All patients have started zoledronic acid through letrozole treatment. Following 4 months of letrozole treatment, a noteworthy increase was observed in TC (p=0.013) and LDL-C (p=0.006) levels compared to baseline values. These elevations reverted to baseline levels after 8 months of treatment. Intriguingly, the observed delayed shifts in TC and LDL-C levels occurred following treatment with zoledronic acid. Furthermore, TC levels decreased significantly after 12 months compared to baseline (p=0.032). HDL-C levels exhibited no significant changes throughout the monitoring periods. TG levels displayed a significant decline after both 8 and 12 months (p=0.015, p=0.018, respectively). Notably, the prior tamoxifen group displayed more pronounced increases in LDL-C and TC levels after 4 months of AI treatment. In contrast, the previous radiotherapy group showed decreased triglyceride levels after 8 and 12 months compared to baseline levels. Letrozole initiation and/or Tamoxifen withdrawal may have adverse effects on lipid profiles, leading to elevated LDL-C and TC levels. Nevertheless, the administration of antiresorption treatment (zoledronic acid) appears to counteract these effects, contributing to an improvement in the lipid profile.