Abstract Sepsis remains the most common associated factor in acute respiratory failure (ARF). Endogenous opiates are known to have both respiratory and cardiovascular depressant effects. Because there is a high level of circulating endogenous opiates in sepsis, the possible role of opioids in the ARF syndrome seen in sepsis was studied. Sixteen piglets were infused with an LD 100 dose (7.5 × 10 10 organisms/kg) of live Escherichia coli (Type 09–41). The pigs were hemodynamically monitored. Serial blood samples were taken for arterial blood gases and lactate. Serial lung biopsies were taken for determining wet/dry lung weight ratios and for histology. Group I ( n = 8): septic shock controls without naloxone; group II ( n = 8): naloxone treated, given as 2 mg/kg/hr intravenous boluses, starting within 1 min of E. coli infusion. All animals died of septic shock. Survivors at 150 min in group II had a higher blood pressure than group I (67.7 ± 5.33 SEM vs 39.0 ± 9.39) and cardiac output was also greater (1.07 ± 0.23 vs 0.25 ± 0.25). By 210 min, group I had no survivors ( 0 8 ) while 3 8 in group II survived. Pulmonary vascular resistance in group II at 90 and 120 min (870.8 ± 274.1 and 942.5 ± 12.9, respectively) was lower than in group I (2868.3 ± 843.6 and 4156 ± 1067). The PO 2 was markedly better in group II and at 90 min; controls had a PO 2 70.7 ± 13.0, while group II had a PO 2 111.4 ± 8.4 ( P < 0.05). PCO 2 levels showed a progressive rise in group I from 39.25 ± 1.4 to 49.4 ± 8.57. Group II showed a reverse trend and PCO 2 values went from 41.4 ± 1.57 to 32.93 ± 2.59. There was no increase in wet/dry lung weight ratios in both groups I and II. Histology showed only mild congestive hyperemia and no pulmonary edema. Naloxone improves oxygenation probably on the basis of improved hemodynamics and reduction of shunting. The rise in PCO 2 may in part reflect the respiratory depressant effects of endogenous opioids and the reversal with naloxone is consistent with this hypothesis.