The neuropeptide alpha-melanocyte-stimulating hormone (alpha-MSH) is a proopiomelanocortin derivative that has potent anti-inflammatory influences within the brain. The aim of the present research was to determine if there are changes in blood concentrations of this peptide in patients with acute traumatic brain injury (TBI) or subarachnoid hemorrhage (SAH). Concomitantly, we recorded clinical parameters and measured blood concentrations of the proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha). Twenty-three patients were enrolled in this study--18 had TBI and five SAH. Blood samples for determination of alpha-MSH and TNF-alpha were collected daily from day 1 to day 4 after injury. Baseline concentration of plasma alpha-MSH in patients with acute brain injury of either traumatic or vascular origin was significantly lower than in controls. Patients with TBI or SAH had similar alpha-MSH concentrations and the peptide remained consistently low over four post-injury days. Circulating TNF-alpha on day one was measurable in all patients and there was a negative correlation between plasma TNF-alpha and alpha-MSH. Alpha-MSH was measured again after the acute phase in eight patients. The peptide was substantially increased in all subjects except for two who had an unfavorable outcome. From the well-known protective anti-inflammatory influences of alpha-MSH in the host, reduction in this circulating peptide may have detrimental consequences in brain injury. The data raise the possibility that restoration of normal circulating alpha-MSH through administration of the peptide could be beneficial in patients with brain injury.