This is the first detailed description of the neuropathology of a patient with xeroderma pigmentosum/Cockayne syndrome complex (XP/CS). This 6-year-old boy's clinical course, followed from infancy to death, is compared with that of the eight other known cases of XP/CS. Normal at birth, he developed the cutaneous sun sensitivity of XP in infancy and the infantile CS phenotype in early childhood. He had the characteristic CS facies, cachexia, failure of somatic and brain growth, spasticity, ataxia, pigmentary retinopathy, hearing loss, mixed peripheral neuropathy, and myopathy. Like his clinical phenotype, the neuropathology was also that of CS despite an XPG genotype. His brain weighed 350 grams (considerably less than the expected weight at birth) and revealed hydrocephalus, tigroid-type demyelination, dystrophic calcification and widespread neuronal loss and gliosis with hyperchromatic glial and endothelial nuclei. Peripheral nerve showed myelinopathy with axonal degeneration, and skeletal muscle had mixed myopathic and neuropathic features. Ophthalmic pathology disclosed cataracts, iris and ciliary body atrophy, inner retinal atrophy and gliosis, retinal pigment epithelial atrophy, and optic nerve atrophy. Molecular studies, which have appeared elsewhere, do not provide full understanding of the pathophysiology of the postnatal growth failure, cachexia, precocious aging, selectivity of tissues affected (such as myelinated axons), and other manifestations of this devastating illness.