The antibody response to the main chromatographic component IV of sperm whale myoglobin in mice has been shown to be under the control of both H-2-linked and non-H-2-linked genes, using an assay which measures antibody concentration independent of affinity. The effect of non-H-2 background genes was such that for a given H-2 haplotype, mice of the A background were higher responders than those of the B10 background. Among congenic mice of all the same background, mice of haplotypes H-2d,s were high responders, while those of haplotypes H-2k,b,q were low responders. Use of intra-H-2 recombinant strains B10.A, B10.A(5R), A.TL, and D2.GD allowed mapping of at least two H-2-linked Ir genes, both within the I region, one tentatively mapping in I-A, designated Ir-Mb-1, and one mapping to the right of I-E and left of H-2D, designated Ir-Mb-2. Strains bearing both genes or only Ir-Mb-1 were high responders, while those bearing Ir-Mb-2 were intermediate responders. When the concentration of antimyoglobin antibodies which bound to [14C]-fragment (132-153) of myoglobin was measured in the same sera described above, levels in the B10.A sera were low like those of the B10.BR rather than intermediate between the levels of the B10.BR and the high responding B10.D2, as for myoglobin, whereas levels in the D2.GD sera were still high. It is therefore suggested that the 2 or more genetically defined H-2-linked Ir genes each control the response to a different chemically defined determinant or group of determinants on myoglobin. Further studies with other fragments are in progress to test this hypothesis.