Abstract NADP-dependent malate dehydrogenase (MDH) has been found to exist in two isozymic forms in mouse tissues. The two isozymes differ in electrophoretic mobility and tissue and subcellular location. The isozyme predominating in heart tissue is located in the mitochondrial fraction and the isozyme predominating in liver tissue is located in the supernatant fraction of tissue homogenates. In an examination of inbred strains of mice, a genetic variant of the supernatant isozyme was found. The mitochondrial isozyme was not affected by this mutation. Preliminary genetic data indicate that the gene controlling supernatant NADP-MDH is in mouse linkage group II. Animals heterozygous for the alleles controlling the synthesis of NADP-MDH contain at least one hybrid enzyme, intermediate between the two parental forms in electrophoretic mobility. This indicates that the enzyme is composed of subunits.