OBJECTIVES: To study differences among two regimens of estrogen/progestin replacement therapy in post-menopausal women with respect to quality of life, pharmacoeconomics, bleeding pattern, compliance and safety profile. METHODS: A 12 centre, randomized, comparative dose study was conducted in 183 women (mean age: 53.9 years) randomized to one of two treatment arms: Prometrium™ 200mg (n=90) or Provera® 5mg (n=93) administered in a single daily dose for 14 days in a 30 day cycle. All patients received 0.625mg Premarin® for 25 of the 30 days. Quality of life was measured by the Nottingham Health Profile (NHP), Woman’s Health Questionnaire (WHQ), and Short Form 36 (SF-36). RESULTS: Improvements in climacteric symptoms were observed between baseline and month 9 within both groups. All domains within the NHP and WHQ improved significantly for both patient groups (p<0.008) and greater improvements were observed for Prometrium patients in the Menstrual Problems and Cognitive Difficulties domains of the WHQ. While Prometrium patients reported an improvement in the Menstrual Problems domain, Provera patients reported a worsening. The number of cycles with bleeding was significantly higher for the Provera patients (p=0.001). Average nine month societal menopausal costs/patient were $367 ± $120 (Cdn) for Prometrium patients and $360 ± $369 (Cdn) for Provera patients (not statistically significant). Although costs were variable, offsetting savings for Prometrium patients were observed in out-of-pocket expenses and missed time from work. CONCLUSIONS: This study highlights important quality of life and cost aspects of Prometrium and Provera use that may impact longer term compliance when patients use Prometrium + Premarin regimens.