Background: Aromatase inhibitors are the standard adjuvant therapy for postmenopausal women with hormone receptor (HR) positive early breast cancer (EBC). In such patients, a significant reduction in bone density was observed. To stop bone loss, bisphosphonates have a powerful effect on reducing bone resorption and improving the survival of patients with EBC. This study compared potential bone-protection of immediate versus delayed administration of zoledronic acid (ZOL) in patients with EBC receiving adjuvant letrozole. Methods: In a prospective two-arm comparative study, 65 postmenopausal patients with HR⁺ EBC in whom adjuvant letrozole treatment was initiated (2.5 mg/day for 5 years), we included either (45) immediate ZOL treatment or (20) delayed ZOL treatment (both at 4 mg every 6 months). Patients in the delayed ZOL group received ZOL only for fracture or increased bone pain or developed bone mineral density (BMD)T score = or < -2.0. We aimed to assess the change in lumber spine BMD every 3 months for 24 months for both immediate and delayed arm patients, in addition to evaluating bone pain deterioration and the disease-free survival (DFS). Results: Analysis of data showed significant differences between immediate and delayed arms in the first three BMD measurements with mean values were -1.55± 0.4 vs. -1.9± 0.2, -1.56± 0.3 vs. -2.5± 0.3, and -1.4±0.3 vs. -3.5± 0.3 with p<0.002, 0.001, 0.0001 respectively. Despite ZOL administration in delayed arm patients was initiated 6 months later than immediate arm patients, improvement of BMD was detected in delayed arm later on. The median DFS for immediate and delayed arms were 39± 0.6 months and 21± 0.4 months respectively with p<0.001 in both. Although, in pre-ZOL bone pain scoring, most patients of delayed arm (75%) were found to have a score of 3 compared to 51.1% of immediate arm, significant improvement in bone pain scores in both arms separately after ZOL administration was noted with p-values 0.031, and 0.025 respectively. Conclusions: Immediate ZOL administration prevented bone loss, improved bone pain, and ameliorate DFS in postmenopausal women with HR⁺ EBC receiving adjuvant letrozole. Clinical trial information: PACTR202112813934276.