A short period of combined deficiency of vitamins E and C causes profound central nervous system (CNS) dysfunction in guinea pigs. For this report, CNS histopathology was studied to define the nature and extent of injury caused by this double deficiency. Weanling guinea pigs were fed a vitamin E-deficient or -replete diet for 14 d. Then vitamin C was withdrawn from the diet of some guinea pigs. Four diet groups were thus formed: replete, vitamin E deficient, vitamin C deficient, and both vitamin E and C deficient. From 5 to 11 d after institution of the doubly deficient diet, 9 of 12 guinea pigs developed paralysis, and 2 more were found dead. The remaining guinea pig in the doubly deficient group and all animals in the other 3 groups survived without clinical impairment until the experiment was terminated at 13-15 d. Brains and spinal cords were serially sectioned and stained for examination. Only the combined deficiency produced damage in the CNS. The damage consisted mainly of nerve cell death, axonal degeneration, vascular injury, and associated glial cell responses. The spinal cord and the ventral pons in the brainstem were most severely affected, often exhibiting asymmetric cystic lesions. Several features of the lesions suggest that the primary damage was to blood vessels. These results indicate that the paralysis and death caused by combined deficiency of vitamins E and C in guinea pigs is caused by severe damage in the brainstem and spinal cord.