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To document changes in serum levels of the vasoactive and immunoregulatory neuropeptides, calcitonin gene-related peptide (CGRP) and substance P, in human postoperative sepsis and to determine whether levels correlate with outcome.Prospective, descriptive cohort study with no interventions.Surgical intensive care unit and clinical research center.The study included 61 patients with sepsis after major visceral surgery (survivors, n = 37; nonsurvivors, n = 24) and 23 control patients without sepsis.Serum levels of CGRP and substance P were measured by specific enzyme-linked immunoassays over the course of sepsis. Postoperative sepsis was associated with a significant increase in CGRP serum levels. Systemic CGRP levels were significantly higher in nonsurvivors than in survivors as early as day 1 of sepsis and remained significantly elevated in nonsurvivors throughout the entire course of sepsis. Substance P levels were also elevated in sepsis patients as compared with controls, but significant differences between survivors and nonsurvivors were only observed during the final phase of sepsis.High systemic CGRP levels were associated with lethal outcome already at the onset of sepsis, whereas high substance P levels were identified as late predictive indicators of lethal outcome. These results are consistent with the view that the neuropeptides, CGRP and substance P, may be involved in the pathogenesis of sepsis.