Anti-microtubule drugs that cause mitotic arrest and subsequent apoptosis of cancer cells are frequently used to treat breast cancer patients with advanced or metastatic diseases. However, patient response rates to this class of chemotherapeutic agents vary significantly. Identification of cellular and genetic factors that are associated with the sensitivity to anti-microtubule drug treatment would have great clinical implications. Our previous studies have demonstrated that the neuronal protein, synuclein-gamma (SNCG), plays oncogenic roles in breast carcinogenesis and is abnormally expressed at high levels in advanced and metastatic breast carcinomas but not expressed in normal or benign breast tissues. In this study, we show that responses of 12 breast cancer cell lines to paclitaxel-induced mitotic arrest and cytotoxicity highly correlate with SNCG expression status. SNCG-positive cells exhibit a significant higher resistance to paclitaxel-induced mitotic arrest than SNCG-negative cells (p<0.01). Moreover, we demonstrate that down-regulation of SNCG expression directly increased the effectiveness of anti-microtubule drug-induced cytotoxicity in breast cancer cells without altering cell responses to doxorubicin. These new findings suggest that SNCG expression in breast carcinomas is probably a causal factor contributing to the poor patient response to paclitaxel treatment.