The regulation of compensatory hemodynamic, inflammatory, and metabolic counter-regulatory responses to traumatic injury (trauma/hemorrhage [tx/hem]) and subsequent inflammatory challenges during the post-tx/hem period relies on balanced activation of neuroendocrine and opioid pathways. Pharmacological interventions during the rescue period as well as during the early post-tx/hem period that target these regulatory pathways can potentially affect the activation or efficacy of compensatory mechanisms. Their impact on mechanisms involved in these responses has not been well defined. We examined the impact of morphine and ketamine on immediate hemodynamic responses to tx/hem as well as on the integrity of host defense mechanisms at day 5 post-tx/hem. Morphine (10 mg/kg), ketamine (18 mg/kg), or saline (0.3 ml) were injected intraperitoneally at 15 min post-tx/hem (soft tissue injury and fixed pressure hemorrhage, 40 mmHg, 60 min) and 15 min before lactated Ringer’s fluid resuscitation (LRFR, 2.4× total blood volume removed). Morphine, but not ketamine, produced effective and sustained analgesia. Morphine and ketamine impaired the rise in mean arterial blood pressure (MABP) during LRFR and increased 48-h mortality (2- to 3-fold). Morphine and ketamine markedly (40%-80%) attenuated the systemic LPS- (100 μg/100 g body weight) induced TNF response at day 5 post-tx/hem. Morphine attenuated LPS-induced lung and spleen TNF expression, whereas ketamine enhanced spleen TNF expression but did not alter lung responses. Subsequent studies demonstrated that the morphine-induced impairment of the response was not due to altered cytokine responses during the early post-tx/hem period but that they could be restored and 24 h mortality could be reduced by increasing the volume of LRFR (2-fold). These results indicate that morphine and ketamine analgesia compromise the hemodynamic and host defense responses after tx/hem, directly affecting mortality and morbidity during the recovery period.