The ability of murine helper T cells primed to the antigen, sheep erythrocytes (SRBC) to cross-react with burro erythrocytes (BRBC) in the in vitro anti-trinitrophenol (TNP) response to TNP-RBC was shown to be under genetic control. Although non-H-2 genes were shown to influence the absolute level of helper activity assayed after SRBC priming, the extent of cross-reaction of SRBC-primed helpers with BRBC was shown to be controlled by an H-2-1inked Ir gene(s). H-2 haplotypes were identified which determined high, intermediate, or low response to the cross- reacting determinants and the gene(s) controlling the cross-reaction tentatively mapped to the K through I-E end of the H-2 complex. Helpers primed in F(1) mice of high x intermediate or high x low responder parents were tested for cross-reaction using B cells and macrophages (Mphi) of parental haplotypes. In each case the extent of cross-reaction was predicted by the H-2 haplotype of the B cells and Mphi, establishing the expression of the Ir gene(s) in B cells and/or Mphi a t least, but not ruling out its expression in T cells as well. The low cross-reaction seen when T cells from F(1) mice of high x low responder parents were tested on low responder B cells and Mphi was not increased by the presence of high responder Mphi, indicating the Ir gene(s) is expressed in the B cell a t least although it may be expressed in Mphi as well. These and our previously reported experiments are consistent with the hypothesis that helper T cells recognize antigen bound to the surface of B cells and Mphi in association with the product(s) of Ir gene(s) expressed on the B cell and Mphi.