A number of inbred and congenic resistant strains of mice were immunized with staphylococcal nuclease (Nase). Antibody responses were measured in the sera of the animals by a sensitive method involving inhibition of enzymatic hydrolysis of DNA, High responder strains included A/J, DBA/2, BALB/c, AKR/J, C57BR, and SJL/J. DBA/1 and C57BL/6 mice were low responders. The strain distribution of anti-Nase response potential was compatible with the relevant immune response gene(s) being linked to the murine major histocompatibility complex. Linkage of this response to H-2 was demonstrated by the findings that: (a) the congenic C3H/HeJ and C3H.SW mice were respectively high and low responders; (b) the congenic lines B10.A and B10.D2 were high responders, whereas the C57BL/10 strain was a poor responder; and (c) anti-Nase response potential of F(2) progeny from DBA/1 x SJL/J matings correlated with their H-2 type. Three B10.A recombinant lines were used to map this Ir gene within H-2. B10.A(4R) was a high responder to Nase, whereas B10.A(2R) and B10.A(5R) were both low responders. We wish to propose the name Ir-Nase for the gene(s) controlling antibody responsiveness to this immunogen. Our data indicate that Ir-Nase is located within the same chromosomal segment of the H-2 complex as is Ir-IgG.