Genetic predisposition of SL/Kh mice to spontaneous pre-B lymphomas was investigated in crosses between SL/Kh and NFS/N, another inbred strain of mice lacking endogenous ecotropic provirus and spontaneous lymphoma. (SL/Kh x NFS/N) F1 hybrids developed lymphomas similar to those in SL/Kh but at a lower frequency and with a longer latent period. Of 83 backcross mice to NFS/N, 22 developed hemopoietic tumors: 8 were diffuse lymphoblastic lymphomas; 2 were myeloid leukemias arising by 12 months of age; and 12 were follicular center cell lymphomas found later in life. Of 6 endogenous ecotropic proviruses in SL/Kh, 2 were expressed in (SL/Kh x NFS) F1 backcrossed to NFS. One, encoded by a 27-kilobase EcoRI fragment, was closely linked to Gpi-1a on chromosome 7 and its expression seemed to be a prerequisite for the occurrence of all types of hemopoietic tumors. Microsatellite analysis of the backcross generation revealed multiple host genetic factors determining susceptibility to tumors. An allele derived from SL/Kh, mapped in the major histocompatibility locus on chromosome 17, was essential for development of early onset tumors. This locus was designated as Esl-1 (early lymphoma of SL-1). On the other hand, follicular center cell lymphomas developed mostly in the backcross mice homozygous for the NFS/N derived allele at the D4MIT17-linked locus, designated as foc-1 (follicular center cell lymphoma-1), on chromosome 4.