Metazoan species diversification in general and the adaptation of parasites to their life-style in particular are due, not only to the evolution of different structural or metabolic proteins, but also to changes in the expression patterns of the corresponding genes. In order to explore the conservation/divergence of transcriptional regulation in the platyhelminth parasite Schistosoma mansoni, we are studying the structures and functions of transcriptional mediators. CREB-binding protein (CBP) and p300 are closely related transcriptional coactivators that possess histone acetyltransferase (HAT) activity that can modify chromatin to an active relaxed state. They are also thought to link transcription factors to the basic transcriptional machinery and to act as integrators for different regulatory pathways. Here we describe the cloning and functional characterization of S. mansoni CBP. SmCBP1 comprises 2093 amino acids and displays a conserved modular domain structure. The HAT domain was shown to acetylate histones with a marked activity toward H4. Functional studies showed that SmCBP1 could interact physically with the nuclear receptor SmFtz-F1 and also potentiated its transcriptional activity in the CV-1 cell line. Screening of the EST and genomic sequence databases with the SmCBP1 sequence allowed us to characterize a second CBP gene in S. mansoni. SmCBP2 shows a high degree of sequence identity to SmCBP1, particularly in the HAT domain. Phylogenetic studies show that these peptides are more closely related to each other than to either mammalian CBP or p300, suggesting that they derive from a platyhelminth-specific duplication event. Both genes are expressed at all life-cycle stages, but differences in their relative expression and structural variations suggest that they play distinct roles in schistosome gene regulation.