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The Womenʼs Health Initiative (WHI) Study of Cognitive Aging studies have investigated the effects of specific treatment regimens containing a combination of conjugated equine estrogens (CEE) and medroxyprogesterone acetate (MPA) or CEE only on longitudinal changes in domain-specific cognitive function in older postmenopausal women. In the previous reports, CEE + MPA had a deleterious impact on verbal memory but appeared to have a positive effect on figural memory over time in older postmenopausal women. The present study tests the possibility that CEE alone (unopposed by MPA) could protect against age-related declines in both verbal and figural memory.This randomized, double-blind, placebo-controlled clinical trial investigated the effects of CEE alone on changes in domain-specific cognitive function and affect in older postmenopausal women. The study was conducted between 1999 and 2004 at 14 WHI clinical centers. The study subjects were 886 postmenopausal women (mean age, 74 years) with prior hysterectomy who were free of probable dementia and were enrolled in the WHI and WHI Memory Study CEE-Alone trial for a mean of 3 years and followed for an additional 2.7 years. Participants were randomized to receive one daily tablet containing CEE, 0.625 mg or a matching placebo. The primary outcome measures were mean differences in annual rates of change of specific cognitive functions and affect, adjusted for time since randomization using analyses of covariance.The data showed that CEE alone had no significant effects on cognitive functions and affect. Compared with the placebo, women in the CEE only group had significantly lower scores on a measure of spatial rotational ability (P < 0.01) after an average of 3 years of treatment, but over the additional 2.7 years of treatment there was a greater rate of improvement in spatial rotational performance indicating some recovery of their initially poorer performance.These findings show that CEE does not improve cognitive domains, including figural memory or affect in postmenopausal women with prior hysterectomy. Accordingly, it does not slow the decline of age-related changes in memory in this population. Spatial rotational ability was lower after 3 years of CE treatment but appears to recover with continued treatment.