The role of non-H-2 gene(s) in the control of the antibody response to three lysozymes was investigated. Upon secondary challenge, A/J (H-2a) mice generated at least a 25-fold greater anti-lysozyme plaque-forming cell response than did B10.A (H-2a) mice. Nearly equal, strong peak primary responses, predominantly IgG in nature, were obtained from both A/J and B10.A mice after a single challenge with lysozyme in complete Freund's adjuvant. However, clear differences in responses are seen within 5 days after the peak primary plaque-forming response and by day 28 at the serum antibody level. B10.A mice never equal their primary responses, whereas A/J mice demonstrate positive immune memory. It appears that a non-H-2 gene(s) that regulates the overall antibody level to a protein antigen becomes manifest only after an initial antibody response.