E2A is a basic helix-loop-helix (bHLH) transcription factor required for B cell lymphopoiesis and implicated in myogenesis and the regulation of insulin expression. As E2A is expressed widely in tissues, tissue-specific downstream effects are thought to result primarily from dimerization with other bHLH proteins. To investigate the degree to which regulation of E2A protein abundance may serve to regulate E2A function, expression of E2A was evaluated using immunohistochemistry on histological sections of primary human tissues. Somewhat surprisingly, nuclear staining for E2A was restricted in all tissues examined, often to a small subpopulation of cells. In some tissues, such as adult liver, expression was absent or Limited to rare infiltrating lymphocytes. E2A-expressing cells were most abundant in lymphoid tissues. In tonsil, lymph node, and spleen, expression appeared most abundant and prevalent among rapidly proliferating centroblasts of the germinal center dark zone. Scattered E2A-expressing thymocytes were more numerous in the thymic cortex than medulla. In developing skeletal muscle, E2A was detectable in striated myotubes but not in more primitive mononucleated progenitors or mature muscle. Differential E2A expression was also noted in proliferating periventricular neuroepithelial cells in the developing brain. These results suggest that regulation of EA abundance complements protein-protein interactions in modulating E2A function.