Alterations of cell-mediated immune responses in the rat produced by 5-day (one 3-min stress session each day for 5 days) and 1-day (three 3-min stress sessions within 12 h) cold water stress administration were investigated. Mitogenic responses to concanavalin A (Con A) and lipopolysaccharide (LPS), interleukin-2 (IL-2) production, CD4+/CD8+ T-cell ratios, and natural killer (NK) cell activity of blood and spleen lymphocytes were increased by the 5-day cold water stress. Responses to Con A and LPS, IL-2 production, and CD4+ and CD8+ percentages of blood and spleen lymphocytes were decreased by the 1-day cold water stress. Corticosterone levels were increased by both the 1-day and 5-day cold water stress. Cold water stress, as a natural stressor, may have its own unique pattern of neuroendocrine changes because of the accompanying body temperature variations that may influence immune functions.