Since the primary PFC response to TNP-Ficoll, a thymus-independent type 2 antigen, displays an important variability in vivo among diverse inbred mouse strains, we used, in the present report, H-2 congenic strains possessing different genetic backgrounds to show that the amplitude of this response is governed by MHC genes, with one regulating locus situated in or near the centromeric part of the I-A subregion. In addition, this H-2 control was largely modulated by gene(s) located outside MHC and IgH haplotypes, as evidenced by the response of recombinant inbred strains (BXH) between the high responder C3H/HeJ and the low responder C57BL/6J. Our results are discussed in terms of humoral regulations and the requirement for self-recognition in cellular interactions which lead to activation of B lymphocytes in the in vivo primary response towards TI-2 antigens.