Background: Randomized trials and a recent meta-analysis suggest that adjuvant bisphosphonates can decrease recurrence and death, primarily in a postmenopausal population. SWOG S0307 compares efficacy of 3 bisphosphonates in early stage breast cancer. Methods: Patients with stage I-III breast cancer receiving adjuvant systemic therapy were randomized to receive 3 years of clodronate (CLOD) (1600 mg po qd), ibandronate (IBAN) (50 mg po qd) or zoledronic acid (ZA) (4 mg IV q month x 6, then q3 months x 2.5 years). The primary endpoint was disease-free survival (DFS). The target accrual of 5,400 gave ≥ 86% power to detect a statistically significant difference (2-sided α = 0.05) among the arms in an ITT analysis. Results: Late rapid accrual led to over-accrual, 6,097 patients were enrolled between 1/06-02/10. Median age was 53 with 58% post-menopausal or age 50+. 77% of tumors were ER positive, 17% HER2 positive, 16% triple negative, and 49% lymph node positive. There were more patients with grade 3/4 events with IBAN (10.5%) than CLOD (8.3%) or ZA (8.8%). Rates of ONJ were highest for ZA (1.2%), then IBAN (0.6%), followed by CLOD (0.3%). Fractures were equal across arms. 73% of patients indicated a preference for oral versus intravenous formulation if all agents showed equal efficacy. At the fourth formal interim analysis, with 56% of 1,314 expected events, the DSMC concluded that there was no realistic chance of a statistically significant difference and recommended early reporting of the trial outcomes. The primary outcome DFS did not differ across arms in a log-rank test (p = 0.71). 5-year DFS was 88% in the CLOD and ZA arms, and 87% in the IBAN arm. Overall survival was 93% in all 3 arms. Additional analyses based on age and menopausal status show no evidence of treatment differences. Conclusions: We found no evidence of differences in efficacy by type of bisphosphonate either in the intent to treat analysis or based on age and menopausal status. Despite differences in the type of toxicity, overall grade differed little across arms. Given that the oral study drugs are preferred by patients and approved elsewhere, efforts to make them available in the U.S. should be considered. Clinical trial information: NCT00127205