Background. Immune dysfunction and post-injury infections are complications associated with thermal injury. Opiates, the analgesic of choice for the treatment of post-burn pain, can also induce similar immune complications. However, the impact of therapeutic opiates on post-burn immune dysfunction is unknown. Materials and Methods. C57BL/6 mice were subjected to a small 6.25% total body surface area (TBSA) burn or sham procedure. The mice were left untreated or treated with morphine sulfate by subcutaneous implantation of an Alzet pump that administered morphine sulfate at a rate of 2 mg/kg body weight/day. Plasma, splenocytes and splenic macrophages were isolated for in vitro analysis 1, 4, or 7 days later. Results. Neither burn injury nor morphine treatment alone significantly altered splenic T-cell proliferation at 1, 4, or 7 days post-injury/treatment. In contrast, morphine treatment of injured mice suppressed splenic T-cell proliferation at 4 and 7 days post-injury/treatment. The suppressed proliferation of T-cells correlated with increased levels of the nitric oxide and an immunosuppressive Th-2 type phenotype. In contrast morphine treatment did not accentuate the suppressed T-cell proliferative responses associated with larger injuries covering 12.5% and 25% TBSA. Splenic macrophage function was unaffected with the exception that LPS-induced nitric oxide production was elevated in the injured mice treated with morphine. Conclusions. These findings demonstrate that those mice treated with a clinically relevant dose of morphine sulfate after an "immunologically insignificant" burn displayed immunosuppression and a Th-2 cytokine profile. Thus, the therapeutic administration of exogenous opiates appears to contribute to the development of post-burn immune dysfunction. © 2005 Elsevier Inc. All rights reserved.