2-Methoxyestradiol (2ME), a metabolite deriving from 17-beta estradiol, is a well-established antiangiogenic, apoptotic and antiproliferative agent in cell cultures and animal models. 2ME may also exert its cytotoxic activity by interacting with tubulin and by causing an impairment of the microtubular system. The aim of this study was to investigate the relative effectiveness of 2ME on mouse neuroblastoma (C1300) and rat glioma (C6) cell lines in inducing morpho-functional changes and alteration of the microtubular system physiology. Cells, cultured in a medium supplemented with increasing 2ME micromolar concentrations, were submitted to morphological investigations, MTT assay and western blot analysis. 2ME-exposed cell lines displayed in comparison with control cells, morpho-functional changes such as reduction in cell number, a globular/shrunken shape, retraction or absence of cytoplasmic processes, inhibition of cell growth and cell decreased viability. Interestingly, all changes detected were more evident in C1300 cells than in C6 cells. Western blot analysis showed that the total and the tyrosinated a-tubulin expression was reduced more intensely in the C1300 than in C6 cells; whereas the acetylated a-tubulin expression did not significantly decrease in either cell lines. Results demonstrate that 2ME is more effective in neural cells than in glial cells. The alteration of total and tyrosinated a-tubulin expression suggests that 2ME effectiveness could be strictly related to an impairment of microtubule system physiology resulting in morpho-functional changes, block of mitosis and cell death.