Shingles can cause chronic neuropathic pain (postherpetic neuralgia) long after skin lesions heal. To investigate its causes, we quantitated immunolabeled sensory neurites in skin biopsies from 18 subjects with and 16 subjects without postherpetic neuralgia after unilateral shingles. Subjects rated the intensity of their pain. Punch skin biopsies were evaluated from the site of maximum pain or shingles involvement, the homologous contralateral location, and a site on the back, distant from shingles involvement. Sections were immunostained with anti-PGP9.5 antibody, a pan-axonal marker, and the density of epidermal and dermal neurites determined. The group with postherpetic neuralgia had a mean density of 339 ± 97 neurites/mm2 in shingles-affected epidermis compared with a density of 1,661 ± 262 neurites/mm2 for subjects without pain. Neurite loss was more severe in epidermis than dermis. Unexpetedly, the lack of contralateral shingles eruptions or pain, correlated epidermis. Contralateral damage ocurred despite the lack of contralateral shingles eruptions or pain, correlated with the presence and severity of ongoing pain at the shingles site, and did not extend to the distant site. Thus, the pathophysiology of postherpetic neuralgia pain may involve a new bilateral mechansm.