1. We show that mouse strains differ widely in susceptibility to tolerance induction and/or immunization (priming) following contact of protein antigens (ovalbumin, human or bovine gamma globulins) with different mucosal surfaces. 2. When compared to a control group pretreated with saline, mice pretreated by the oral (intragastric) route with antigen became significantly less responsive to subsequent parenteral immunization (i.e., tolerant). This was observed in most, but not all, antigen/strain combinations. 3. Similar, although less prominent changes were induced by pretreatments with antigen by the ocular (conjunctival) route. 4. No significant effects were observed following pretreatments by the nasal, vaginal or rectal routes. 5. Genes present in strains selected for multispecific "high" or "low" responsiveness are included among those involved in tolerance induction following mucosal contacts with protein antigens.