To understand the effect of aging on human skin innervation, we investigated intraepidermal nerve fiber (IENF) density of skin biopsies. IENF densities of the distal leg were lower in elderly (> or = 60 years of age) than in young adults (19-39 years of age; 7.80 +/- 0.79 vs 13.55 +/- 0.85 fibers/mm, p < 0.01). A similar trend was also observed in the distal forearm (11.67 +/- 1.55 vs 19.39 +/- 1.60 fibers/ mm, p < 0.001). IENF densities were negatively correlated with age according to multiple linear regression analysis on the entire study population (age range: 19-78 years) with standardized coefficients of -0.462 (p < 0.001) in the distal leg and -0.335 (p = 0.005) in the distal forearm. These findings suggest a significant reduction in IENF densities with age.