The transcription factor signal transducer and activator of transcription 3 (STAT3) is inappropriately activated in the majority of breast tumors, especially in aggressive and invasive ones. In addition to driving the expression of genes promoting malignancy, STAT3 associates with tubulin and can promote cell migration. Because microtubule-targeted drugs are among the most active agents used in the treatment of breast cancer, we examined whether microtubule-based chemotherapy modulates STAT3 activity. When treated with paclitaxel or vinorelbine, breast cancer cells with constitutive activation of STAT3 display a loss of STAT3 phosphorylation, and paclitaxel disrupts the interaction of STAT3 with tubulin. Paclitaxel also inhibits cytokine-induced STAT3 activation. This effect is specific for microtubule-targeted agents, because other chemotherapeutic drugs, such as doxorubicin, have no effect on STAT3. The loss of STAT3 tyrosine phosphorylation is also reflected in an inhibition of expression of STAT3 target genes. This effect is not restricted to breast cancer, because similar effects are also seen in ovarian cancer and prostate cancer cells. Thus, in addition to their role in disrupting microtubule function, microtubule-targeted agents also suppress STAT3 signaling. This may be an important component of their activity, raising the possibility that microtubule targeted therapy may be particularly effective in tumors characterized by STAT3 activation.