Mice of five inbred strains (BALB/c, C3H, C3Hf, DBA/2, and C57BL/6) of both sexes, mated and virginal, were examined for the incidence, severity, and location of dystrophic cardiac calcinosis (DCC) at various ages. Three hybrids, B6C3F1, C3B6F1, and CC3F1 of both sexes, all mated, were likewise studied. Excepting DBA/2, females of the inbred strains acquired the lesion at a much earlier age than males; DCC appeared in young DBA/s mice of both sexes. DCC in BALB/c mice was almost exclusively epicardial and occurred with equal frequency and severity in mated males and females, with higher incidence but lesser extent in virginal females. The occurrence was highest, the degree most severe, and the location exclusively myocardial in C3H and C3Hf mated females, irrespective of parity, whereas virginal females of these strains were entirely free of disease even after administration of exogenous progesterone. Involvement of males, also myocardial, was relatively minimal, especially in C3Hf mice. Over half the DBA/2 mice were affected, regardless of sex or mating; calcinosis appeared in the epicardium and/or myocardium, predominantly in the myocardium. Strain C57BL/6 was completely devoid of the lesion, as were the two hybrids thereof, B6C3F1 and C3B6F1. The hybrid of BALB/c and C3H showed a high incidence of minimal involvement, exclusively myocardial and limited to breeding females, indicating dominance of the C3H gene(s). Renal calcinosis was uncommon among BALB/c mice but was frequently found in C3H, C3Hf, and DBA/2 strains. Pulmonary calcinosis was rare and limited to C3H and C3Hf female breeders. Mated C3H females fed increasing amounts of fat showed a concomitant rise in incidence and severity of the cardiac lesions. Progression of the lesion from necrotic myocardial fibers to fibrocalcific masses is illustrated, as is formation of the renal deposits.