Psychological stress is believed to exacerbate inflammatory skin disease but the underlying mechanisms are poorly understood. We investigated the impact of acute social stress--Trier public speaking test--on: epidermal Langerhans' cell (LC) frequency; and cutaneous nerve fiber expression of protein gene product (PGP) 9.5 and calcitonin gene-related peptide (CGRP). Thirty-six healthy volunteers each had a pair of baseline 6 mm biopsies taken from sun-protected buttock skin. A second pair of biopsies was taken from contralateral buttock 4 hours (n=5) or 24 hours (n=15) after the Trier stressor. Controls (n=16) did not perform the Trier and had biopsies 24 hours apart. One of each pair of biopsies (baseline; 4 or 24 hours) was processed for counts of epidermal CD1a(+) LC; the other examined for PGP 9.5 and CGRP expression. We observed a significant (P<0.01) 16.4% reduction in epidermal LC frequency 24 hours post-stressor as compared with baseline; there was no significant change from baseline in non-stressed controls. At 24 hours, PGP 9.5 and CGRP were increased (P=0.025) and reduced (P=0.03), respectively, from baseline in the stressed group compared with controls. These data suggest that acute social stress reduces epidermal LC frequency and modulates cutaneous neuropeptide expression thereby supporting the concept of a "brain-skin" axis.