Objective: To compare the efficacy and tolerability of a novel oral constant estrogen plus intermittent progestogen hormone replacement therapy (HRT) regimen to a continuous combined HRT regimen in postmenopausal women. Methods: Subjects were randomly assigned to receive treatment with either constant 17β-estradiol (E 2), 1 mg, plus intermittent norgestimate (NGM) 90 μg (3 days off, 3 days on) ( n=221) or E 2 2 mg/norethisterone acetate (NETA) 1 mg ( n=217) for 1 year. Treatments were evaluated based on the incidence of hot flushes and uterine bleeding. Results: Both regimens had similar bleeding profiles and provided comparable vasomotor symptom relief. However, breast discomfort and edema were experienced by twice as many subjects who received E 2/NETA. Conclusions: The constant E 2/intermittent NGM regimen was well tolerated and possesses similar efficacy compared with a continuous combined E 2/NETA regimen and may be considered whenever HRT without withdrawal bleeding is deemed appropriate.