Background. CD8+ T cells have putative roles in the regulation of adaptive immune responses during infection.The purpose of this paper is to compare the status ofCD8+ T cells inMultiple Sclerosis (MS) andChronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME). Methods.This preliminary investigation comprised 23 CFS/ME patients, 11 untreated MS patients, and 30 nonfatigued controls. Whole blood samples were collected from participants, stained with monoclonal antibodies, and analysed on the flow cytometer. Using the following CD markers, CD27 and CD45RA (CD45 exon isoform 4), CD8+ T cells were divided into na¨ıve, central memory (CM), effector memory CD45RA− (EM), and effector memory CD45RA+ (EMRA) cells. Results. Surface expressions of BTLA, CD127, and CD49/CD29 were increased on subsets of CD8+ T cells fromMS patients. In the CFS/ME patients CD127was significantly decreased on all subsets ofCD8+Tcells in comparison to the nonfatigued controls. PSGL-1was significantly reduced in the CFS/ME patients in comparison to the nonfatigued controls. Conclusions.The results suggest significant deficits in the expression of receptors and adhesion molecules on subsets of CD8+ T cells in both MS and CFS/ME patients. These deficits reported may contribute to the pathogenesis of these diseases. However, larger sample size is warranted to confirm and support these encouraging preliminary findings.