Transcription of the human complement receptor type 2 (CR2/CD21) gene is controlled by both proximal promoter and intronic elements. CR2 is primarily expressed on B cells from the immature through mature cell stages. We have previously described the presence of an intronic element that is required for both cell- and stage-specific expression of CR2. In this study, we report the identification of a cell type-specific repressor element within the proximal promoter. This repressor sequence is shown by linker scanning mutagenesis to comprise an E box motif. By supershift analysis this element binds members of the basic helix-loop-helix family of proteins, in particular E2A gene products. Mutational analysis demonstrates that binding of E2A proteins is critical for functioning of this repressor. Thus, E2A activity is key not only for early B cell development, but also for controlling CR2 expression, a gene expressed only during later stages of ontogeny.