This study aimed to explore the effects of continuous-combined estradiol 1 mg/drospirenone 2 mg (E2D) on cognitive performance in healthy, recently postmenopausal women. METHODS: A 6-month randomized, double-blind, placebo-controlled study was carried out in a university research center. Participants were 23 healthy postmenopausal women aged 49 to 55 years. Cognitive performance was assessed with a computerized cognitive battery administered to all participants on 0, 12, and 26 weeks. Functional magnetic resonance imaging was performed on 13 participants before and after treatment using tasks of verbal fluency and mental rotation. RESULTS: E2D was not associated with an overall effect on cognitive performance. Functional magnetic resonance imaging results showed no difference between the groups for verbal fluency or mental rotation task performance at baseline. The mental rotation task was associated with increased blood oxygen level-dependent signalling in the placebo group in both occipital lobes and in the left superior parietal lobe after 26 weeks (P <0.05), with no changes over time seen in the treatment group. The total menopausal symptom and sexual function domain scores improved after treatment in women randomized to E2D compared with the placebo group (both P <0.05). Similarly, systolic blood pressure, weight, and body mass index were significantly lower in women randomized to E2D at 26 weeks (P <0.05). CONCLUSIONS: E2D has no detrimental effect on cognitive performance in early postmenopausal women. E2D significantly improves menopausal symptoms, sexual function, systolic blood pressure, and weight. ? 2013 by The North American Menopause Society.