This study demonstrates that Ha-ras Val12 oncogene overexpression sensitizes NIH/3T3 fibroblasts to lovastatin (LOV) cytotoxicity. This sensitization is through apoptosis, which was characterized by increasing CPP32 (caspase-3) activity and DNA fragmentation. Bcl-2 overexpression increased the resistance of the Ha-rastransformants to LOV and rescued the cells from apoptosis, further confirming that the LOV-sensitive cells died of apoptosis. Further analysis showed that Ha-rasactivity inversely correlated with WAF1 activity. LOV treatment suppressed Ha-rasactivity but induced WAF1 activity and disrupted the cell population in G 0 /G 1 and S phases. The Ha-rastransformants expressing either dominant negative Ras Asn17 or Raf-1 CB4 showed reverted susceptibility to LOV. These data confirm the involvement of Ras and demonstrate that Raf-1 signalling is required for LOV-induced cell death. Taken together, the possible action of LOV-induced apoptosis is through suppressing Ha-rasactivity and increasing WAF1 activity, which alters cell cycle progression and finally activates suppressed apoptotic pathway in a Fas/Fas-L- and p53-independent fashion.