The effect of skeletal muscle injury (SMI) on cardiovascular and O2 transport responses to hemorrhage (HS) were examined in anesthetized pigs. Bilateral hindlimb muscle was injured 75 minutes before HS was started at a rate of 0.75 mL/min kg until a total of 30 mL/kg (40% estimated total blood volume) had been removed. The reductions in cardiac index (CI), left ventricular stroke work, and oxygen delivery (Do2) and the increase in plasma lactate concentration following HS were exacerbated by SMI such that although oxygen consumption was maintained after HS it fell after SMI + HS. The deleterious effect of SMI on the response to HS was greater than that recorded previously following somatic brachial nerve stimulation (BNS). Thus, in order to achieve a given reduction in CI and Do2 or a rise in Shock Index (heart rate divided by systolic blood pressure) to approximately 3, a blood loss of 40% was needed after HS; this was reduced to 36% by the addition of BNS, whereas a loss of only 29% was needed when SMI was introduced. The mechanism of the deleterious effect of SMI is unclear although a change in the distribution of regional blood flow and a rise in the critical oxygen delivery may be implicated.