We have used a novel method of chromosomal exclusion to map the recessive mutation juvenile cystic kidney (jck) to mouse chromosome 11 using an intercross between (C57BL/6J x DBA/2J) F1jck/ + mice. The severity of polycystic kidney disease (PKD) in the intercross progeny was significantly more variable than that found in the parental C57BL/6J strain, suggesting that a modifier locus or loci introduced from DBA/2J affects expression of jck. Two regions--one from DBA/2J on chromosome 10 and a second from C57BL/6J on chromosome 1--are associated with inheritance of a more severe PKD phenotype. The finding of a highly significant association of inheritance of a C57BL/6J-related locus with disease severity, with a maximal QTL analysis lod score of 16.8, was unexpected; this result suggests that inheritance of both this locus and at least one DBA/2J locus results in the more severe phenotype, presumably as a consequence of a direct or indirect interaction between their protein products.