Activity of α-glycerolphosphate dehydrogenase (EC 1.1.1.8), linked to cytoplasmic nicotinamide adenine dinucleotide, is higher in brains of BALB/cJ mice than in brains of C57BL/6J mice. The magnitude of the difference is dependent on both the age and brain region of the mice. Maximal differences are observed at 20 days of age and are detected in the cerebellum, with only marginal differences occurring in other brain regions. Kidney and liver of BALB/cJ mice have higher enzyme activity than those of C57BL/6J mice, whereas muscle-enzyme activity is lower in BALB/cJ mice than in C57BL/6J mice. In addition to differences in activity, α-glycerolphosphate dehydrogenase in BALB/cJ mice is more sensitive to heat denaturation. The half-life for the enzyme at 50° in BALB/cJ, (BALB/cJ x C57BL/6J)F 1 hybrid, and C57BL/6J mice is 1, 1.7, and 3 min, respectively. Genetic analysis of the mode of inheritance of the heat-sensitive enzyme reveals that the trait is determined by a single autosomal gene. Genetic analysis of the activity of α-glycerolphosphate dehydrogenase in the cerebellum indicates that the mechanism of inheritance for this trait involves two or more genes and that one of these genes also confers heat sensitivity on the enzyme. The affect of these genes on enzyme activity is codominant and additive.