The objective of this study was to address the cellular and psychological mechanisms underlying previously observed changes in natural killer (NK) cell cytotoxicity associated with chronic stress. We compared 28 current and former spousal caregivers of patients with Alzheimer's disease (AD) and 29 control subjects. NK cells were enriched (E-NK) using a 4-step procedure that resulted in a cell preparation consisting of 88.2% NK cells. These cells were then incubated with either recombinant interferon-gamma (rIFN-gamma) or recombinant interleukin-2 (rIL-2) for 65 hours. Although an average of over 3 years had elapsed since the death of the patient with AD for the former caregivers, current and former caregivers did not differ in the E-NK cell responses to rIFN-gamma and rIL-2. However, the E-NK cell response for the combined caregiver group was significantly suppressed compared with controls, which is consistent with a previous report from our laboratory. Higher E-NK cell responses to each cytokine were associated with heightened levels of positive emotional and tangible social support, independent of levels of depression. Preliminary data suggest that defects of NK cell function in response to rIFN-gamma and rIL-2 as a consequence of caregiver stress may be independent of non-NK cells. Finally, our data are consistent with other studies regarding the role of social support in immune modulation.