The translationally controlled tumor protein (TCTP) is conserved in all eukaryotes studied thus far. Recent evidence points to an important role for TCTP in the induction of cell proliferation in animals through an interaction with G proteins. TCTP may also constitute an intercellular secreted signal that modulates the immune response in the vertebrates. Because of its sequence conservation and ubiquity, the analysis of its amino acid sequence divergence between different taxa may provide insight into the structural constraints on the evolution of this protein. In the present study, we analyzed the phylogeny of TCTP sequences from a wide range of organisms and found that, with some exceptions, the groupings formed were consistent with the evolutionary history. Indeed, at the level of lower-order taxa, the groupings are in agreement with their established phylogeny, thus indicating that the substitution rates of the TCTP residues varied evenly between members of the same clade. Predicted three-dimensional structures of representative TCTPs, based on the reported 3D structure of Schizosaccharomyces pombe, indicated that these proteins are highly conserved among diverse taxonomic groups. However, analysis of the primary structure indicated subtle differences in the domain-forming pocket that potentially interacts with G proteins, particularly among Diplomonadidae, Apicomplexa, and other parasites of vertebrates. These differences support the notion that these specific TCTPs could block the normal immune response by acting as dominant negative mutants. Structural differences were also observed in a reported sequence of TCTP from Plasmodium knowlesi, in which the presence of an extra alpha-helix could also interfere in the interaction with G proteins.