Paclitaxel is known to cause Raf‐1 kinase activation resulting in Bcl‐2 inactivation, which is a target substrate in pathways controlling apoptosis. We report here that v‐Ha‐ras‐transformed NIH 3T3 cells were significantly more sensitive to treatment of paclitaxel than its parental cells. This paclitaxel‐induced growth inhibition was found to be linked to increase Raf‐1/ERK activity. Moreover, Raf‐1 protein knock‐down makes cells more resistant to paclitaxel treatment. The expression of Spry2, which is known to modulate the Ras/Raf/MAPK signal either directly or through feedback regulation, was down‐regulated after the treatment of paclitaxel. As determined by analysis of Spry2 cytosine phosphate‐guanosine (CpG) island promoter methylation, down‐regulation of Spry2 appeared to be associated with altered methylation. Interestingly, siRNA‐mediated knockdown of Spry2 potentiated paclitaxel‐induced growth inhibition of v‐Ha‐ras‐Transformed NIH 3T3 cells. Taken together our results suggest that paclitaxel can induce growth inhibition by inducing high level of Raf‐1 kinase activity through the down‐regulation of Spry2.