Strains A/J and C57BL/6J (B6) differ in susceptibility to many neoplasms and infectious agents, with B6 mice generally being more resistant. Glucocorticoids protect against some of these pathologies. We examined the distribution of adrenocortical corticosterone (CS), the major endogenous glucocorticoid in mice, in these strains, using anti-CS serum. A distinct strain difference was found. B6 adrenals exhibited abundant CS-positive cells in cord-like arrays while A/J adrenals contained fewer, randomly arranged CS-positive cells. To quantify these results, each adrenal cortex was divided into eight sectors and each sector was classified as to phenotype. Ninety-three percent of the sectors of B6 cortices exhibited the cord-like pattern, whereas only 15% of the sectors of A/J cortices exhibited this pattern. These differences are consistent with a hypothesis that A/J mice are relatively deficient in the prophylactic activities of endogenous glucocorticoids. Adrenal glands from (C57BL/6J x A/J)F1 hybrid mice had approximately equal proportions of areas exhibiting each phenotype, indicating codominant alleles for this trait. We propose the name Cor for this gene. Thirty AXB and BXA recombinant inbred (RI) lines of mice derived from A/J and B6 progenitors were examined for CS immunostaining. Twenty-eight of them had either predominantly A/J-like or predominantly B6-like phenotypes. These RI data support either of two hypotheses. Hypothesis 1 emphasizes the nearly complete concordance of the RI lines with progenitor phenotypes and proposes that a single Cor gene regulates the distribution of CS-positive cells. Using this model, the strain distribution among RI lines implies linkage of Cor to a region on chromosome 6, 27-37 cM from the centromere. Hypothesis 2, which gives greater weight to the two RI lines with intermediate numbers of CS-positive cells, postulates an epistatic interaction between two Cor loci.