H-2b mice fail to respond to some bird lysozymes (prototype: hen egg-white lysozyme (HEL)) while showing normal responsiveness to other closely related bird lysozymes (prototype: ringed-neck pheasant lysozyme (REL)). H-2b mice also fail to respond to human lysozyme (HUL). Previous studies have shown that differential HEL:REL responsiveness is associated with two genetic loci within H-2, one mapping to the left of I-B and one to the right. Present studies, in which equal positive response is found to HEL and REL in H-2ba and H-2bf mice, indicate that a mutation at H-2K is associated with the loss of ability to discriminate between HEL and REL. The presence of at least one controlling locus outside H-2 is suggested by studies with recombinant inbred strains (RI) of C57BL/6 and C57L (a strain which responds to HEL although H-2b). Two such RI with H-2 derived from the C57BL/6 parent respond to HEL while one RI with H-2 derived from C57L does not respond.