Given the bidirectional nature of the communication between the immune and hypothalamic‐pituitary‐adrenal (HPA) systems, we examined whether animals that exhibit differences in HPA responses to stress would also exhibit differences in their plaque‐forming cell (PFC) responses to sheep red blood cells (SRBC). Neonatally handled (H) animals exhibit lower HPA responses to a number of acute stressors in adulthood compared to nonhandled (NH) animals. Furthermore, these differences also emerge as a function of chronic, intermittent cold stress. We hyphothesized that H and NH animals may exhibit differences in the PFC response to SRBC under conditions of acute and/or chronic stress (H CHR and NH CHR). Exposure to acute (4 hr) cold decreased PFC responses in both H and NH animals compared to nonstressed H and NH animals. The decrease in PFC response produced by chronic, intermittent cold stress was similar in H and NH animals and was not different from that found in acutely stressed animals. In H CHR animals reexposed to cold stress, the PFC response was not different from acutely stressed or chronically stressed H and NH animals. In contrast, the PFC response in NH CHR animals reexposed to cold stress was lower than all other groups studied. Thus, neonatal handling prevented prior chronic stress‐induced suppression of the PFC response to a subsequent stress. These data suggest that there may be subpopulations of individuals in whom prior chronic stress does not exacerbate the immune suppression produced by acute stress. However, those chronically stressed individuals in whom immune suppression does occur may be more vulnerable to infection and disease. © 1996 John Wiley & Sons, Inc.