Peroxisome proliferator-activated receptors (PPAR) belong to the nuclear hormone receptor superfamily of ligand-dependent transcription factors. Recent results have shown that agonists of PPARgamma, such as troglitazone (TGZ), can inhibit cell proliferation and promote cell differentiation independent of PPARgamma. In the present study, we provide evidence that TGZ may bind directly to EGFR and trigger its signaling and internalization independent of PPARgamma. Detailed studies revealed that prolonged incubation with TGZ effectively attenuated EGFR signaling by targeting the receptor to the endo-lysosomal degradation machinery. Although the extracellular signal-regulated kinase-signaling pathway was transiently activated by TGZ in EGFR overexpressing cancer cells, inhibition of EGF-induced Akt phosphorylation most likely accounted for the growth arrest of tumor cells caused by TGZ at pharmacologically achievable concentrations. Therefore, we have provided a new line of evidence indicating that TGZ inhibits cell proliferation by promoting EGFR degradation and attenuating Akt phosphorylation.