Background Obesity prevention is a major public health priority. Despite the health risks associated with weight gain, there has been a distinct lack of research into effective interventions to prevent, rather than treat, obesity particularly at high risk life stages such as menopause in women. This paper describes the rationale for and design of a 2-year randomized controlled trial (RCT) (the 40-Something Study) aimed at testing the feasibility and efficacy of a relatively low intensity intervention designed to achieve weight control in non-obese women about to enter the menopause transition. Methods and design The study is a parallel-group RCT consisting of 12 months of intervention (Phase 1) and 12 months of monitoring (Phase 2). Non-obese pre-menopausal healthy females 44-50 years of age were screened, stratified according to Body Mass Index (BMI) category (18.5-24.9 and 25-29.9 kg/m2) and randomly assigned to one of two groups: motivational interviewing (MI) intervention (n?=?28), or a self-directed intervention (SDI) (control) (n?=?26). The MI intervention consisted of five consultations with health professionals (four with a Dietitian and one with an Exercise Physiologist) who applied components of MI counselling to consultations with the women over a 12 month period. The SDI was developed as a control and these participants received print materials only. Outcome measures were collected at baseline, three, 12, 18 and 24 months and included weight (primary outcome), waist circumference, body composition, blood pressure, plasma markers of metabolic syndrome risk, dietary intake, physical activity and quality of life. Analysis of covariance will be used to investigate outcomes according to intervention type and duration (comparing baseline, 12 and 24 months). Discussion The 40-Something study is the first RCT aimed at preventing menopausal weight gain in Australian women. Importantly, this paper describes the methods used to evaluate whether a relatively low intensity, health professional led intervention will achieve better weight control in pre-menopausal women than a self-directed intervention. The results will add to the scant body of literature on obesity prevention methods at an under-researched high-risk life stage, and inform the development of population-based interventions.