<b><i>Background:</i></b> The effects of the glucocorticoid and progesterone receptor agonist megestrol on declarative memory, and the ability of phenytoin to block these effects, were assessed. <b><i>Methods:</i></b> Healthy volunteers received each medication combination (placebo and megestrol, phenytoin and megestrol, and placebo and placebo) using a randomized, crossover design. The Rey Auditory Verbal Learning Test assessed declarative memory. <b><i>Results:</i></b> Megestrol was associated with a significant reduction in declarative memory (<i>p</i> = 0.0008), which was attenuated by phenytoin, and was associated with significant cortisol suppression compared to placebo (<i>p</i> &#x3c; 0.001). <b><i>Conclusion:</i></b> Changes in memory and cortisol suppression were found in healthy volunteers given megestrol.