Objective: To evaluate progesterone and differing progestogen treatments with respect to cognitive function and mood in healthy women in early menopause. Design: This was a randomized, placebo-controlled, double-blind trial with longitudinal assessments of neuropsychological function and mood at baseline and 6 and 24 months. In addition to placebo, there was a progesterone and three progestogen treatment groups, one with estradiol augmentation. Materials and Methods: Subjects were recruited from regions served by two university medical centers in the midwestern U.S. Prospective subjects who had used hormone replacement therapy previously, who had increased risk for cancer, or had a potentially contributing psychiatric or neurological condition were excluded. One hundred forty-two healthy women who had not experienced a menstrual cycle in at least 12 months following either surgery or natural menopause were randomized to one of five treatment groups, including micronized oral progesterone, 400 mg/day; norethindrone (19-nortestosterone), 1.0 mg/day; medroxyprogesterone acetate (3 methyl analogue progesterone), 10 mg/day; medroxyprogesterone acetate, 10 mg/day plus micronized estradiol, 1 mg/day; and placebo for 24 months. Eighty-four women completed the study. A comprehensive neuropsychological protocol was administered to all subjects at pretreatment baseline and after 6 and 24 months of treatment. The outcome measures included tests of executive function abilities, attention, episodic memory, motor function, and mood. Repeated measures analyses of variance for each domain of functioning were performed to identify changes from baseline at 6 and 24 months. Results: There was no difference between groups at baseline in age (F = .48, ns), educational level (F = .66, ns), IQ estimate (F = 1.56, ns), or level of depression (F = .1.19, ns). Mean group scores at baseline on the Hamilton depression scale were well below clinical threshold and ranged from 5.4 to 7.8 (overall M= 6.3). There was no treatment effect on the neuropsychological measures: executive planning ability (F = 1.63, ns); working memory (F = 0.26, ns); verbal attention (F = 0.17, ns); spatial attention (F = .41, ns); episodic memory (F= 0.57, ns); and fine motor speed (F = 0.23, ns). However, there was a significant group effect for mood (F = 2.77, p < .05). This latter effect was attributable to a decline in total mood disturbance in the norethindrone group from baseline (M = 20.9) to 6 months (M = 5.2), and this decline was maintained until study termination at 24 months (M = 6.3). Conclusion: These findings indicate that short- and long-term progesterone and progestogen therapy, alone or in combination with estradiol, do not affect cognition positively or negatively in healthy, postmenopausal women. On the other hand, norethindrone produced improvement in overall mood, independent of cognitive function, and this specific effect persisted for the duration of the trial. This improvement in mood is particularly notable given that women were not clinically depressed at baseline and may reflect the greater androgenic nature of this particular progestogen.