The Women's Health Initiative Study of Cognitive Aging (WHISCA) was a two armed, randomized, placebo controlled, clinical trial designed to assess the efficacy of postmenopausal hormone therapy on age related changes in specific cognitive functions. WHISCA was an ancillary study to the Women's Health Initiative (WHI) and the WHI Memory Study (WHIMS) and enrolled 2302 women aged 66 to 84 years (mean 73.9; standard deviation 3.8) who did not meet criteria for dementia. Women were randomly assigned by the WHI to hormone treatment (unopposed conjugated estrogens (CEE) 0.625 mg/day if they were without a uterus; CEE combined with medroxyprogesterone acetate (MPA) 2.5 mg/day otherwise) or placebo for an average of three years before the first WHISCA assessment. WHISCA investigated the effects of hormone therapy on rates of change over time in memory, other aspects of cognition (language, attention, spatial ability), motor function, and mood. In this paper, we present the study rationale and design, including specific cognitive measures, and the challenges of incorporating WHISCA into an ongoing randomized trial. WHISCA provided a unique opportunity to investigate the potential of hormone therapy to modify age related changes in specific cognitive functions. WHISCA also demonstrated the feasibility of adding a detailed cognitive assessment into an ongoing clinical trial to address an important issue in women's health, despite the challenges of maintaining the integrity of the parent studies, ensuring high retention, and achieving high quality assurance across sites.