The chicken major histocompatibility (B) complex (MHC) affects disease outcome significantly. One of the best characterized systems of MHC control is the response to the oncogenic retrovirus, Rous sarcoma virus (RSV). Genetic selection altered the tumor growth pattern, either regressively or progressively, with the data suggesting control by one or a few loci. Particular MHC genotypes determine RSV tumor regression or progression indicating the crucial B complex role in Rous sarcoma outcome. Analysis of inbred lines, their crosses, congenic lines, and noninbred populations has revealed the anti-RSV response of many B complex haplotypes. Tumor growth disparity among lines identical at the MHC but differing in their background genes suggested a non-MHC gene contribution to tumor fate. Genetic complementation in tumor growth has also been demonstrated for MHC and non-MHC genes. RSV tumor expansion reflects both tumor cell proliferation and viral replication generating new tumor cells. In addition, the B complex controls tumor growth induced by a subviral DNA construct encoding only the RSV v-src oncogene. Immunity to subsequent tumors and metastasis also exhibit MHC control. Genotypes that regressed either RSV or v-src DNA primary tumors had enhanced protection against subsequent homologous challenge. Regressor B genotypes had lower tumor metastasis compared with progressor types. Together, the data indicate that B complex control of RSV tumor fate is strongly defined by the response to a v-src-determined function. Differential RSV tumor outcomes among various B genotypes may include immune recognition of a tumor-specific antigen or immune system influences on viral replication.