HMG-CoA reductase inhibitors and histone deacetylases (HDACs) inhibitors have been shown to induce apoptosis in a variety of cells, which could potentially be used as an anticancer therapy in addition to the designated applications. In the present study, we explored the possible synergistic pro-apoptotic effects and the underlying mechanisms when the two classes of inhibitors were combined. Exposure of HeLa cells to the combined treatment of mevastatin (an inhibitor of HMG-CoA reductase) and trichostatin A (TSA) (an inhibitor of HDACs) synergistically induced apoptosis. Mevastatin treatment transcriptionally and translationally up-regulated RhoA expression in the cells by negative feedback mechanism. While TSA enhanced mevastatin-induced RhoA up-regulation, more importantly, it also accelerated mevastatin-mediated depletion of membrane-bound (geranylgeranylated) RhoA. Moreover, TSA treatment down-regulated protein geranylgeranyl transferase-I (GGTase-I) beta subunit expression, which is one of the key enzymes for protein geranylgeranylation. Taken together, TSA down-regulated GGTase-I beta expression, hence enhanced the statin-induced depletion of geranylgeranylated RhoA, which could be an important mechanism for the synergistic induction of the apoptosis.