The antibody response to the major chromatographic component IV of sperm whale myoglobin (MbIV) has been found to be under H-2-linked Ir gene control in several series of congenic resistant strains of mice on the C57BL/10, A, and DBA/2 backgrounds by using an assay which measures molar concentration of antibody independent of affinity. The H-2d and H-2s mice were high responders, whereas the H-2k, H-2b, and H-2q mice were low responders. High responsiveness was dominant in the (H-2d × H-2b)F1 cross. The genetic control was mapped to within the I (or S, G) regions by the low response of A.TL mice. The presence of two (or more) genes within this region controlling the response was indicated by the intermediate response of the B10.A, A/J, and B10.A(5R) strains, indicating at least one gene to the right of H-2K but left of I-C, tentatively called Ir-Mb-1, and at least one other to the right of I-E but left of H-2D (presumably in I-C), tentatively called Ir-Mb-2. The former of these was further mapped to the I-A subregion by the high responsiveness of the D2.GD mice (which are d in K and I-A and b elsewhere), virtually identical to that of the DBA/2 (H-2d) mice with which these are congenic. This last observation suggests that either Ir-Mb-1 can confer full responsiveness by itself, or that coupled complementation is active. In contrast, Ir-Mb-2 alone confers only intermediate responsiveness. Whether these genes control the response to different determinants on the myoglobin molecule remains the subject of further study. In addition, for a given H-2 haplotype, the response of A background mice was about 5-fold higher than that of B10 background mice. Thus, non-H-2-linked genes also control the level of response. All of the above levels of control, both H-2 and non-H-2 linked, appeared to operate both after a single immunization in complete Freund's and after two subsequent booster immunizations.