We recently demonstrated that aged mice are less likely to survive following traumatic injury and are more immunosuppressed than young mice who sustain comparable injuries. Immunosuppression in severely injured patients and in rodent models of burn injury is associated with a marked elevation in proinflammatory cytokines, including interleukin-6 (IL-6). We reported that after sustaining a moderate-size scald injury, aged mice have higher circulating levels of IL-6 than young, injured mice. As proestrus levels of estrogen have been reported to boost immune responses and attenuate IL-6 production, in the present study, we went on to determine if estrogen replacement in aged female mice restored cellular immunity and proinflammatory cytokine production. After injury, in placebo-treated, aged animals, there was a >75% suppression in the delayed-type hypersensitivity response relative to placebo-treated, sham-injured, aged mice (P<0.05). In contrast, estrogen supplementation before injury yielded a partial recovery in this response, such that the mice were suppressed by only 40% relative to sham-injured, aged mice (P<0.05). There was a fourfold increase in the circulating level of IL-6 in burn-injured, aged mice who received placebo hormone replacement relative to sham-injured mice given placebo (P<0.05). This level of cytokine was lowered by nearly 50% in aged, estrogen-treated mice. Most remarkably, estrogen replacement improved survival from 42% (in the absence of estrogen) to 70% in aged, burn-injured mice. Further investigation will be needed to determine if age- and gender-specific therapies are needed for the treatment of all trauma patients.