We evaluated the effect of antigen feeding on the subsequent primary and secondary anti-ovalbumin (OVA) responses of C57BL/6 and NZB mice. When C57BL/6 mice were given a single 20-mg dose of OVA intragastrically, profound tolerance was observed after challenge, 7 d later, with 125 micrograms of OVA in complete adjuvant or after two injections of 5 micrograms of OVA adsorbed to alum given 7 and 21 d after antigen feeding. OVA-fed NZB mice failed to become tolerant to a primary challenge with OVA in complete adjuvant, but showed a degree of tolerance similar to that of C57BL/6 mice when challenged two or three times with OVA in alum. These studies demonstrate that NZB mice fail to show tolerance at the level of the primary response after antigen feeding; however, they are normally tolerant when a secondary response to a lower dose of antigen is evaluated. This study suggests that, after antigen feeding, different mechanisms of tolerance may be involved in the regulation of primary and secondary responses.