Objective: To evaluate the effects of continuous hormone replacement therapy (HRT) regimens on platelet-tritiated ( 3H-) imipramine binding (Bmax) and mood. Design: Prospective randomized study. Setting: University hospital. Patient(s): Sixty postmenopausal patients. Intervention(s): Randomization to 3 months of daily treatment with tibolone and conjugated equine estrogen (CEE) .625 mg combined either with 2.5 or 5 mg of medroxyprogesterone acetate (MPA). The inclusion criteria–matched patients declined for HRT were prescribed daily alendronate. Pre- and posttreatment blood sampling for Bmax and mood evaluation with the Beck Depression Inventory (BDI) and the State-Trait Anxiety Inventory (STAI) were done. Main Outcome Measure(s): Pre- and posttreatment Bmax and mood scores. Result(s): As compared with baseline, both CEE+MPA regimens and tibolone significantly increased Bmax. The comparisons of percent change from baseline Bmax for the CEE+MPA and tibolone groups were similar. All three HRT regimens improved the BDI significantly, while there were no significant changes in the STAI. In the alendronate group, there were no significant changes in both pre- and posttreatment Bmax and mood scores. Conclusion(s): Continuous treatment with CEE+MPA and tibolone increases platelet 3H-imipramine binding and improves mood. Mood-enhancing effects of tibolone may occur through the serotonergic system, as is the case with estrogen.