Programmed cell death (apoptosis) is critical for the normal development and homeostasis of the immune system. There is increasing evidence that dysregulations of apoptotic pathways are associated with autoimmune disease, including multiple sclerosis (MS). Cellular commitment to apoptosis is partly regulated by the Bcl-2 family proteins, which includes the death antagonists Bcl-2 and Bcl-X(L), and death agonists Bax and Bad. Since the role of these proteins in the pathogenesis of MS is currently unknown, we analyzed their expression profile in peripheral and intrathecal lymphocytes from MS patients and appropriate controls. We observed a significant reduction in the expression ratios of pro-apoptotic to anti-apoptotic Bcl-2 members in both peripheral and intrathecal lymphocytes from MS patients when compared to corresponding ratios in patients with inflammatory or noninflammatory neurologic controls, or healthy individuals. The relative coexpression ratios of these pro- and anti-apoptotic Bcl-2 family proteins in MS were more significant than the expression of individual members. The low cellular expression ratios of pro-apoptotic proteins in MS were confirmed in vitro activated T lymphocytes. Cellular expression of Bcl-2, Bcl-X(L), Bax or Bad in MS patients was independent of the expression of other apoptotic regulatory molecules, such as Fas receptor protein or FLIP. Our findings suggest that the abnormal expression patterns of Bcl-2 family proteins in MS may promote apoptotic resistance of potentially pathogenic, autoreactive lymphocytes, and may allow for continuing cellular proliferation and tissue destruction within the central nervous system.