The impact of chemoprevention trials can be hampered by poor participant compliance with the study medication. We used medication monitoring systems and pill count data to try to establish factors that may predict compliance with the International Breast Intervention Study (IBIS) and whether the participants went on to complete or benefit the trial. Women who took their trial medication in a regular pattern rather than randomly were more likely to be of benefit to the study (p = 0.003). For those women who failed to complete the study, compliance was shown to gradually reduce at each follow-up appointment. The taking of additional prescribed medication and not smoking were important factors in predicting completion (p = 0.04 and p = 0.047, respectively) and benefit (p = 0.037 and p = 0.031, respectively) to the study. Taking these factors into account when advising women at the start of a chemoprevention trial may be helpful in improving compliance.