The aim of the study was to assess the adequacy of pituitary function by determining the plasma concentrations of corticotroph-type (corticotropin, β-endorphin immunoreactive material [β-END IRM], authentic β-END, and β-lipotropin IRM) as well as melanotroph-type (α-melanocyte-stimulating hormone [α-MSH] and N-acetyl-β-END [Nac-β-END] IRM) proopiomelanocortin (POMC) derivatives in patients under septic shock upon administration of corticotropin-releasing hormone (CRH). The objectives were to assess whether an insufficient release of corticotroph- or melanotroph-type POMC derivatives from the pituitary into the cardiovascular compartment correlates with the 28-day mortality rate. Seventeen patients with septic shock but without adrenocortical insufficiency and 16 healthy volunteers were enrolled in the study, and CRH stimulation tests were performed with an i.v. bolus injection of 100 μg human CRH. After treatment with CRH, plasma concentrations of corticotroph-type POMC derivatives increased in survivors and nonsurvivors, melanotroph-type POMC derivatives such as α-MSH or Nac-β-END IRM increased only in survivors in contrast to nonsurvivors. The release of α-MSH and Nac-β-END IRM was suppressed by dexamethasone in survivors but not in nonsurvivors. In patients with septic shock, the response of the pituitary to CRH stimulation in terms of α-MSH or Nac-β-END IRM release was impaired in nonsurvivors compared with survivors or controls. Reduced responses of α-MSH or Nac-β-END IRM to CRH and the invalid suppression by dexamethasone reflect a state of dysfunction of the melanotroph-type POMC system in nonsurvivors. Considering anticytokine and anti-inflammatory effects of α-MSH, this dysfunction may increase the risk of death in patients with septic shock.