Introduction: Metformin may provide therapeutic benefits to patients with various types of malignancy. Through its insulin-sensitizing effect, metformin can also reduce weight in non-diabetic populations.Purpose: Our research aimed at evaluating the effect of metformin as an adjuvant therapy to aromatase inhibitor (letrozole) on estradiol and other biomarkers serum levels in postmenopausal obese breast cancer women.Patients and methods: This controlled study involved 45 postmenopausal breast cancer females who were assigned into three arms: the control arm (arm 1; n= 15 obese women) which received letrozole only (2.5 mg/day); the metformin arm (arm 2; n= 15 obese women) which provided a similar letrozole dosage in addition to metformin (2000 ± 500 mg/day); and the lean arm (arm 3; n= 15) which received letrozole. The intervention duration was 6 months. Blood samples were obtained at zero time and six months later for the measurement of serum estradiol, osteocalcin, insulin, leptin, lactate, and fasting blood glucose. Results: After the intervention, the metformin arm had significantly lower osteocalcin and fasting blood glucose levels than both the control and the lean arms (p<0.0001, p<0.0001, respectively). The metformin and lean arms had significantly lower fasting insulin levels, homeostatic model assessment of insulin resistance (HOMA-IR), estradiol, and leptin concentrations than the control arm (p = 0.0064, p = 0.0020, p<0.0001, and p<0.0001, respectively). We observed non-significant variation in serum lactate levels among the three study arms.Conclusion: Metformin might represent a promising adjuvant therapy to letrozole in postmenopausal women with breast cancer.ClinicalTrials.gov Identifier: NCT05053841/Registered September 23, 2021 - Retrospectively