Objectives The study investigated the effect of hormone replacement therapy (HRT) on cognitive processes in healthy, naturally postmenopausal women. Method Participants were 64 volunteer postmenopausal women (27 in HRT, 37 in non-HRT group). Groups were matched for age, level of education and postmenopausal period. Duration of HRT was more than 12 months. Cognitive processes were measured through 44 scores obtained from Wechsler Memory Scale-Revised, Line Orientation Test, Cancellation Test and Raven Standard Progressive Matrices. All of these tests had been studied with respect to their psychometric properties in the Turkish culture [for review, Karakaş S. BİLNOT battery: research and development of neuropsychological tests. Ankara, Turkey: Dizayn Ofset; 2004]. Results Multivariate analysis of variance was performed where HRT and estradiol level were predictive (independent) variables and test scores were predicted (dependent) variables. The studied variables did not have a significant effect on a broad spectrum of neuropsychological scores that measured immediate and delayed visual and verbal memory, visuospatial perception and orientation, sustained attention/vigilance, visual search and scan, impulsivity and response speed, executive functions and general intelligence. Logistic regression analysis demonstrated a prediction rate of 86.89% of HRT status; the model was, however, based on four scores whose scientific relevance could not at this point be ascertained. Conclusion The research design of the present observational study applied control techniques to demographic (age, level of education), menopausal (length of menopausal period, duration of HRT), and hormonal variables. The cognitive changes that some studies found concerning the effect of replacement therapy could not be found when the potentially confounding variables were thus controlled.