Background: Despite a 50% reduction in the risk of breast cancer (BC) for tamoxifen (T) vs. placebo (P), many women at risk of BC do not adhere to the 5 year course. Using prospectively-collected data from the double-blind NSABP P-1, we evaluated whether patient-reported outcomes were associated with drug adherence, and whether baseline behavioral risk factors modified those associations. Methods: 13,338 women at high risk of BC were randomly assigned to T vs. P (20 mg/day); we analyzed the 11,064 enrolled more than 3 years before trial unblinding 5/98. Mixed effects logistic regression was used to evaluate whether baseline and 3-month (mo) SF-36 mental (MCS) and physical (PCS) quality of life scales, depressive symptoms (CES-D), and possible treatment-related symptoms (BCPT symptom scales) predicted 12-mo drug adherence (using over 75% of assigned medication), accounting for Gail model estimated breast cancer risk and education; and whether associations were modified by baseline smoking status, alcohol consumption, body mass index (BMI, continuous variable), T vs. P, and age (continuous variable). Results: At 12 mo, 10,572 women were expected to be on therapy (excluding patients who never initiated therapy or experienced protocol required discontinuation); 84.2% were adherent. Sexual symptoms at 3 mo were associated with reduced adherence, but only among younger women (for example at age 45, odds ratio (OR) 0.8, p=.048); other symptoms predicted greater adherence among normal weight (OR=1.5 per 1 point, p=.016) but not among overweight women; 3-mo PCS predicted higher adherence among smokers (OR=1.4 per 10 points, p=.02), 3-mo MCS predicted adherence among women assigned to P (OR=1.4 per 10 points, p<.001). No significant associations were found with CES-D. Conclusions: Quality of life and symptoms at 3 months were associated with chemoprevention adherence at 12 months, and the associations differed according to age, treatment, BMI, and smoking status. Behavioral risk factors and patient-reported outcomes will help identify particular patients who may need greater adherence support. Clinical trial information: NCT00003906.