Non-steroidal anti-inflammatory drugs (NSAIDs) have been shown to reduce the risk of colorectal cancer (CRC). They are also known to induce the regression of colorectal adenomas, which are precursors to CRC. Despite these evidences, the exact mechanism by which NSAIDs exerts its anti-oncogenic effect is not completely understood. Using a focus formation assay, here we show that sulindac sulfide, a NSAID, specifically inhibits cell transformation mediated by oncogenic Ha-Ras, but not by other established oncogene products such as v-Src, Galpha12, and Galpha13. Our results suggest that the ability of sulindac sulfide to suppress transformation is confined to specific oncogenic pathways. Further studies of the sulindac-resistant oncogenic pathways may lead to identification of novel therapeutic agents that are effective in the prevention or treatment of CRC.