Polyketide synthases (PKSs) of Mycobacterium tuberculosis are increasingly being seen as producers of virulence factors that are important for pathogenesis by the bacterium. Thus, the phenolphthiocerol synthase PKS cluster of M. tuberculosis is responsible, in part, for the synthesis of a virulence determinant called phthiocerol dimycocerosate (PDIM). Here, we provide evidence that the PpsE protein, which is part of that cluster, interacts with the type II thioesterase TesA of M. tuberculosis. The interaction was demonstrated by employing a two-hybrid system, and confirmed using a GST (glutathione S-transferase) pull-down' assay after both proteins had been purified to homogeneity. Based on the present findings, a revised model for the processing of polyketides during the synthesis of PDIM is presented.