The present study shows that the incubation of human aortic smooth muscle cells (HASMC) and HepG2 cells with atorvastatin and mevastatin as HMG-CoA reductase inhibitors potentiated the interferon-γ (INF-γ)-induced group IIA phospholipase A₂ (sPLA₂-IIA) expression in a dose- and time-dependent manner. The effect of statins on sPLA₂-IIA expression was reduced by mevalonate, farnesyl pyrophosphate and geranylgeranyl pyrophosphate. Inversely, inhibitors of the farnesyl transferase and geranylgeranyl transferase-I mimicked the effects of statins. Clostridium difficile toxin B (TcdB), Y-27632 and H-1152, functioning as inhibitors of Rho proteins and Rho-associated kinase, also augmented the sPLA₂-IIA expression in combination with IFN-γ. The same effects were observed when inhibitors of mitogen-activated/extracellular response protein kinase kinase (MEK), PD98059 or U0126 were used. Further, the Janus kinase-2 (Jak2)-specific inhibitor, AG-490 and inhibitors of nuclear factor-κB (NFκB) abrogated the sPLA₂-IIA elevating effects of statins, TcdB and PD98059 in the presence of IFN-γ. This cytokine alone increased the NFκB p65 and CAAT-enhancer-binding protein-β (C/EBP-β) activity in HASMC nuclear extract, but only C/EBP-β was further augmented when the cells were incubated in addition to IFN-γ with atorvastatin, H-1152, PD98059 or U0126. Moreover, after the incubation of cells with atorvastatin and IFN-γ the stability of sPLA-₂IIA mRNA significantly increased in comparison to those after incubation with IFN-γ alone. In conclusion, the obtained data suggest that (i) the expression of sPLA₂-IIA is negatively regulated by RhoA/Rho-associated kinase and MEK/ERK signaling pathways and (ii) statins, because of their ability to down-regulate these pathways, can potentiate the IFN-γ-induced sPLA₂-II expression at transcriptional and post-transcriptional levels.