Apolipoprotein E (apoE), a plasma lipoprotein involved in lipid metabolism, is also proposed to have important functions within the central and peripheral nervous systems. To investigate the function of apoE in the peripheral nervous system, we examined the structure of sciatic nerves in apoE-deficient (apoE KO) mice. In the normal peripheral nervous system, apoE is produced by nonmyelinating Schwann cells, suggesting a role for apoE in the support of unmyelinated thermal and nociceptive sensory afferents. Using electron microscopy, we have found that apoE KO mice have abnormal and reduced numbers of unmyelinated axons within the sciatic nerve. ApoE KO unmyelinated axons are irregularly shaped and separated by very little Schwann cell cytoplasm. ApoE KO myelinated fibers and myelin are ultrastructurally normal. Consistent with these morphological findings, apoE KO mice display reduced sensitivity to noxious thermal stimuli. These data provide in vivo support for the hypothesis that apoE promotes neuronal health and survival.