Although microtubule interacting agents inhibit spindle dynamics, thereby leading to a block in mitosis, we report that low concentrations of these drugs result in differential mitotic effects. Microtubule-stabilizing agents including Taxol, epothilone B, and discodermolide produce aneuploid populations of A549 cells in the absence of a mitotic block. Such aneuploid populations are diminished in an epothilone B-resistant cell line. In contrast, microtubule-destabilizing agents like colchicine, nocodazole, and vinblastine are unable to initiate aneuploidy. The aneuploid cells result from aberrant mitosis as multipolar spindles are induced by the stabilizing drugs, but not by destabilizing agents. The results suggest that the mechanism underlying aberrant mitosis may not be the same as that responsible for mitotic block, and that the former determines the sensitivity of cells to Taxol-like drugs.