Activation of mature B cells via Ag receptor cross-linking induces transient expression of the transcription factor Egr-1. Although the activating signals leading to Egr-1 induction have been studied extensively, little is known about the genes that are placed further downstream within this activation cascade and that are transcriptionally regulated by Egr-1. To identify such target genes, we established Egr-1-overexpressing transfectants from the murine B cell line K46 and from human Ramos B cells. All clones derived from K46 B cells showed increased expression of CD44. Most interestingly, expression of CD95 (Fas/Apo-1) and of CD23 was down-regulated in all K46 transfectants. As a consequence, they became resistant to apoptosis induced by anti-CD95 Ab treatment. Similarly, the Egr-1-expressing Ramos cells showed reduced levels of CD95 expression. Thus, Egr-1 seems to control the expression of downstream target genes not only as a transcriptional activator, but also as a repressor molecule. In B cells, Egr-1 therefore plays a critical role in integrating the short-lived signal delivered by triggering of the Ag receptor into phenotypic changes, including repression of CD95 and CD23 transcription.