Vitamin E (VE) deficiency is accompanied by myopathy in various animal species including man. Although gene expression profiles related to degenerative and regenerative processes in different kinds of myopathies have been studied, no global expression profile for skeletal muscle subject to VE deficiency has previously been reported. In the present study, Affymetrix GeneChip technology was used to obtain such a profile. Two groups of male rats were fed with either a diet deficient in VE or a control diet. Differential gene expression was monitored at five time-points over 430 days, with all animals individually profiled. Out of approximately 7000 genes represented on the Genechip, 56 were found to be up-regulated in response to VE deficiency in at least four consecutive time-points from as early as 91 days of deficiency. Up-regulated genes included muscle structure and extra cellular matrix genes, as well as anti-oxidative, anti-inflammatory and anti-fibrotic genes. Our data show that molecular transcription might provide a very early marker to detect oncoming degenerative conditions in VE deficiency. They provide further insight into possible molecular mechanisms underlying VE deficiency in skeletal muscle, and reveal the activation of an intensive protection program that can explain the long maintenance of muscle structure during deficiency.