Paclitaxel is an anticancer drug used in the treatment of ovarian, breast, head and neck, lung, and prostate cancer. We investigated the anti-platelet activity of paclitaxel in vitro as well as a possible anti-platelet mechanism. Paclitaxel inhibited washed rabbit platelet aggregation induced by collagen in a concentration-dependent manner, with an $IC_{50}$ of $59.7{pm}3.5$. However, it had little effect on platelet aggregation mediated by arachidonic acid, U46619, a thromboxane (TX) $A_2$ mimic, or thrombin, suggesting that paclitaxel may strongly inhibit collagenmediated signal transduction. In accordance with these findings, paclitaxel blocked collageninduced cytosolic calcium mobilization, arachidonic acid liberation, and serotonin secretion. In addition, it inhibited arachidonic acid-mediated platelet aggregation by about 37% by interfering with $TXA_2$ synthase as measured by the formation of arachidonic acid-mediated $TXA_2$ and prostaglandin $D_2$, as well as cyclooxygenase-1 and $TXA_2$ synthase activity assays. Taken together, these results point to a cellular mechanism for the anti-platelet activity of paclitaxel through the inhibition of $TXA_2$ synthase and cytosolic calcium mobilization. This may contribute to the beneficial effects of paclitaxel on the cardiovascular system.