Previous studies show an association between increased plasma cortisol levels and aging, a process which is also associated with some deterioration of cognition. Animal studies demonstrated damage to pyramidal cells in the hippocampus, secondary to increased cortisol secretion. Conditions in which high cortisol plasma levels are encountered suggest an association between elevated cortisol levels and cognitive impairment. 34 patients drug free for at least 10 days, were challenged by 0.5mg dexamethasone. Pre- and post-challenge cortisol plasma levels were determined by RIA. Cognitive functioning was assessed by the GDS (34 subjects) and later also by the MMSE (17 subjects). Mean GDS score was 5.2 +/- 1.1 (Mean +/- SD) and mean MMSE score was 11.3 +/- 5.8. Mean preDEX and postDEX cortisol plasma levels were 17.03 +/- 6.67 micrograms/dl and 9.95 +/- 6.70 micrograms/dl respectively. Grouping patients by severity of dysfunction, we found that the more severely impaired patients had significantly higher postDEX cortisol levels 7.04 +/- 6.25 vs 12.87 +/- 5.96 (t = -2.7 P less than 0.009 for the GDS scale and 5.74 +/- 6.1 vs 13.82 +/- 6.32, (t = 02.63 P less than 0.019 for the MMSE scale) but no significant difference for preDEX cortisol levels. The Index of HPA Responsivity, defined as: (PreDEX Cortisol-PostDEX Cortisol)/Pre DEX Cortisol+PostDEX Cortisol), was significantly lower for the more impaired patients indicating a less responsive HPA axis in those patients. Pearson correlation between the Index vs the GDS and MMSE scores was -0.43 (F = 7.11, P less than 0.012, n = 34) and 0.49 (F = 4.89, P less than 0.043, n = 17) respectively. Age did not seem to play an important role in this sample. These findings support a relationship between plasma cortisol levels and cognitive impairment. The Index of Responsivity, a dynamic measure of the system, is suggested for future studies.