Mechanisms that contribute to increased female susceptibility to multiple sclerosis can be studied in the murine model of experimental autoimmune encephalomyelitis (EAE). In this report, we compared oral tolerance induction in male and female B10.PL mice using fed myelin basic protein (MBP) Ac1–11 peptide or a high‐affinity analogue, Ac1–11[4Y]. We found that fed Ac1–11[4Y] peptide, but not native Ac1–11, could limit cellular infiltration into the central nervous system (CNS) and protect male mice from EAE, an effect that was completely obviated by castration. In contrast, female mice could not be orally tolerized or protected from EAE with either peptide. Tolerance induction in males was reflected by the appearance of Ac1–11[4Y]‐reactive splenocytes that produced a sharply increased ratio of transforming growth factor (TGF)‐β:interleukin (IL)‐2 and induced bystander suppression. These data directly demonstrate gender differences in regulatory T cells, and support the concept that androgens are involved in governing oral tolerance to EAE. J. Neurosci. Res. 55:432–440, 1999. © 1999 Wiley‐Liss, Inc.