Dystrophic cardiac calcinosis (DCC) occurs among certain inbred strains of mice and involves necrosis and subsequent calcification as response of myocardial tissue to injury. Using a complete linkage map approach, we investigated the genetics of DCC in an F(2) intercross of resistant C57BL/6J and susceptible C3H/HeJ inbred strains and identified previously a major predisposing quantitative trait locus (QTL), Dyscalc1, on proximal chromosome 7. Analysis of inheritance suggested, however, that DCC is influenced by additional modifier QTL, which have as yet not been mapped. Here, we report the identification by composite interval mapping of the DCC loci Dyscalc2, Dyscalc3, and Dyscalc4 on chromosomes 4, 12 and 14, respectively. Together, the four Dyscalc loci explained 47% of the phenotypic variance of DCC, which was induced by a high-fat diet. Additive epistasis between Dyscalc1 and Dyscalc2 enhanced DCC. Examining recombinant inbred strains, we propose a 10-cM interval containing Dyscalc1 and discuss potential candidate genes.