IFN‐β is anticipated to have an important function in mucosal tolerance, as it is one of the major cytokines produced by plasmacytoid dendritic cells, and has recently been suggested as central to the maintenance of mucosal homeostasis. Here, we have investigated whether oral tolerance is dependent on endogenous IFN‐β by feeding low‐dose self‐antigen myelin basic protein to IFN‐β^−/− mice with subsequent induction of experimental autoimmune encephalomyelitis (EAE). Our study shows that oral tolerance was readily induced in IFN‐β^−/− mice compared with their wild‐type littermates (IFN‐β^+/+). The non‐self‐antigen ovalbumin induced oral tolerance in both groups. These data indicate that endogenous IFN‐β is not required for induction of oral tolerance, whereas delivery of recombinant IFN‐β results in significant reduction in clinical score of EAE. Oral tolerance induction was associated with lower production of antigen‐specific IFN‐γ, no shift toward antigen‐specific Th2, Th17 or TGF‐β response was observed. Oral tolerance in IFN‐β^−/− mice was also associated with the induction of regulatory and memory T cells in the mucosal‐associated immune organs, however this was not a prerequisite for establishment of oral tolerance.