The incidence of herpes zoster increases markedly with advancing age, and this appears to be causally related to an age-dependent decline in varicella-zoster virus (VZV)—specific cellular immunity. Psychologic stress has also been linked to the occurrence of herpes zoster, but the mechanism involved has not been investigated. This study examined the relationship between major depression and VZV-specific cellular immunity by comparing VZV-specific responder cell frequency (RCF) in adults with major depression (n= 11) to that in age- and sex-matched nondepressed controls (n= 11) and in a larger group of nondepressed adults who were ≥60 years old. VZV-specific RCF in depressed patients was markedly reduced compared with the RCF in matched controls (t= 2.7,P< .02). In fact, the levels of VZV-specific RCF in the depressed patients were comparable in magnitude to the low levels found in adults ≥60 years of age. These data indicate that major depression is associated with a marked decline in VZV-specific cellular immunity.