BACKGROUND: Exercise has favorable effects on biomarkers associated with a lower risk of breast cancer, however it is unclear if higher doses of exercise provide additional effects. No clinical trial has systematically examined how different exercise volumes influence the mechanisms underlying breast cancer etiology. The Breast Cancer and Exercise Trial in Alberta (BETA) - a follow-up study to the Alberta Physical Activity and Breast Cancer Prevention (ALPHA) Trial - is examining how a one-year, high versus moderate volume aerobic exercise intervention influences several biomechanisms hypothesized to influence breast cancer risk in a group of postmenopausal women. Secondary aims are to compare intervention effects on psychosocial and quality of life outcomes as well as understand exercise adherence at 12 and 24 months, and maintenance of all study outcomes at 24 months. METHODS/DESIGN: The BETA Trial is a two-center, two-armed randomized controlled exercise intervention trial conducted in 400 previously inactive, postmenopausal women aged 50-74 years, in Alberta, Canada. Participants were randomly assigned to a one-year aerobic exercise intervention of either high volume (300 minutes/week) or moderate volume (150 minutes/week). Blood draws and accelerometry were performed at baseline, six and 12 months. Baseline and 12-month measurements were taken of adiposity (including dual energy X-ray absorptiometry and computed tomography scans), physical fitness, dietary intake, self-reported physical activity and sedentary behavior, quality of life, perceived stress, happiness, sleep, and determinants of exercise adherence. Exercise maintenance was assessed and all study measurements were repeated at 24 months. Blood will be analyzed for endogenous estrogens, insulin resistance indicators, and inflammatory markers. DISCUSSION: The BETA Trial will compare the impact of a high versus moderate volume of aerobic exercise on a variety of biological, physiological, and psychological outcomes of relevance to postmenopausal women. A tightly controlled exercise intervention and objective outcome measurements are methodological strengths. The BETA Trial will inform future prevention initiatives by assessing adherence to a high volume of exercise over 12 months by postmenopausal women, and the ability of these women to maintain activity over the longer-term. The ultimate objective is to inform public health guidelines for reducing breast cancer risk through physical activity. CLINICAL TRIALS REGISTRATION NUMBER: NCT01435005.