The Tax protein of human T-lymphotrophic virus (HTLV)-1 activates expression of the HTLV-1 long terminal repeat through a DNA element that resembles the cellular cyclic AMP-regulated enhancer (CRE)(1,2). Tax contains a transcriptional activation domain(3), but its ability to activate gene expression depends on interactions with cellular CRE-binding proteins such as CREB. Whether Tax can activate the expression of cellular CRE-containing genes has been controversial. Here we show that Tax can activate both the HTLV-1 and consensus cellular CREs, and propose that this activation may occur through mechanisms that are differentially dependent on CREB phosphorylation. Tax not only increases the binding of CREB to the viral CRE but also recruits the transcriptional co-activator CBP4,5 in a manner independent of CREB phosphorylation. In contrast, association of Tax with the cellular CRE occurs through CBP which, in turn, is recruited only in the presence of phosphorylated CREB.