We report the first comprehensive 3D QSAR study of a large, structurally diverse set of compounds that act as atypical thrombopoietin (TPO) mimics by interacting with the transmembrane domain of the TPO receptor, c-MPL. These agonists of c-MPL were superimposed according to a pharmacophore hypothesis, resulting in 3D QSAR models of high statistical significance. The pharmacophore-based superimposition and comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were used to derive the QSAR models relating structure to the published in vitro bioactivities of the TPO mimics. The CoMFA and CoMSIA models gave high correlation coefficients of the bioactivities with the derived fields, resulting in robust prediction of agonist activity of the superimposed compounds. The models have been interpreted in terms of the requirements for binding to the transmembrane domain of the TPO receptor.