Background: The MA32 study (NCT01101438) investigated whether 5-years of metformin improves invasive disease-free survival in early-stage breast cancer (BC). Non-adherence to endocrine therapy (ET) and medications for chronic conditions is common, and increases with drug toxicity and polypharmacy. This secondary analysis evaluates rates and predictors of early discontinuation of metformin, placebo, and ET among participants with HR positive BC. Methods: Patients with high-risk non-metastatic BC were randomized to 60 months of metformin (850 mg BID) or placebo. Patients were administered bottles of metformin/placebo every 180 days. Metformin/placebo compliance was defined as a bottle dispensed at month 48 or later (i.e., medication supplied for 54 months). The ET compliance analysis included patients with HR positive BC who received adjuvant ET with start and stop date reported and was defined as > 48 months of use. Associations of baseline covariates with drug compliance and with ET adherence were examined using multivariable models. Results: Among the 2,521 HR-positive BC patients, 32.9% were non-compliant to study drug. Non-compliance was higher among patients on metformin vs. placebo (37.1% vs. 28.7%, p<0.001). Reassuringly, compliance to ET was similar between treatment arms (28.4% vs 28.0%, p=0.86). Patients who were non-compliant to endocrine therapy, were more likely to be non-compliant to study therapy (38.8% vs. 30.1%, p<0.0001). In a multivariable analysis, study drug non-compliance was increased with metformin vs. placebo (OR=1.43, 95% CI, 1.21-1.70; p<0.0001); grade 1 or greater GI toxicity during the first year (70.9% vs. 53.2%; OR=1.20, 95% CI, 1.01-1.44; p=0.044); lower age (age < 50 OR = 1.44, 95% CI, 1.21 – 1.71; p<0.01) and higher body mass index (BMI > 30, OR=1.49, 95% CI, 1.25 - 1.77; p<0.0001). Study drug non-compliance was decreased with prior receipt of chemotherapy (OR = 0.68, 95% CI, 0.50–0.84; p<0.001). Non-compliance with endocrine therapy was associated with increased non-compliance to study drug (OR: 1.47, 95% CI, 1.20, 1.70, p < 0.0001). Study drug (metformin vs placebo) non-compliance was not associated with endocrine therapy non-compliance (OR=0.97, 95% CI, 0.80-1.17; p=0.74). Conclusions: While non-compliance was higher among patients on metformin, it was still considerable among patients on placebo. Among other factors, development of GI toxicity and non-adherence to ET were associated with non-adherence to study drug. Many BC patients on ET are prescribed metformin and other oral medications for the treatment of chronic conditions. Reassuringly, non-adherence to study drug did not impact endocrine therapy adherence. Attention to global medication adherence is needed to improve BC and cardiovascular outcomes in cancer survivors. Clinical trial information: NCT0110143.