a-Tocopheryl succinate (a-TOS), a redox-silent analogue of vitamin E, inhibits malignant mesotheliomas (MM) in a pre-clinical model. Here we investigated the underlying mechanism. Exposure of MM cells to a-TOS triggered apoptosis at higher and inhibited proliferation at lower concentrations, while this effect was not observed in non-malignant mesothelial cells. Sub-apoptotic doses of a-TOS caused down-regulation of fibroblast growth factor receptor-1 (FGFR1) selectively in MM cells, while the effect on FGFR2 was only marginal. FGF1 and FGF2 enhanced MM cell proliferation that was suppressed by a-TOS. Over-expression of E2F1, a transcriptional factor of FGFR1, but not its dominant-negative counterpart, partially blocked the inhibitory activity of a-TOS on MM cell proliferation. Our data suggest a novel mechanism by which a clinically intriguing agent selectively suppresses proliferation of cancer cells, as shown here for the untreatable mesotheliomas.