Introduction: Pharmacological restriction of secretory group IIA phospholipase A₂ (sPLA₂-IIA) expression is thought to be beneficial in the treatment of inflammatory diseases such as sepsis and septic shock. In this study we investigated the effects of activated protein C (APC) on sPLA₂-IIA expression, phosphorylation of extracellular signal-regulated kinase (ERK) 1/2, and on DNA-binding activities of nuclear factor-κB (NF-κB) and CCAAT box enhancer binding protein-β (C/EBP-β) in human aortic smooth muscle cells (HASMC). Materials and methods: To achieve elevated sPLA₂-IIA production as occurring during inflammation, HASMC were stimulated with interferon-γ (IFN-γ) alone and in combination with other inductors, thus modeling the strong sPLA₂-IIA elevation by inflammation. Results and conclusions: APC inhibited the stimulated expression of sPLA₂-IIA in HASMC dose-dependently (1-300 nM). At the same time, APC increased the phosphorylation of ERK 1/2 and decreased NF-κB and C/EBP-β DNA-binding activities in these cells, as compared with respective stimulated controls. Reverse transcriptase-polymerase chain reaction and cell-based ELISA reveal an endothelial protein C receptor (EPCR) expression in HASMC. Application of antibodies against EPCR and protease-activated receptor-1 (PAR-1) reduced the APC-induced ERK 1/2 activation and the treatment of cells with a PAR-1 antagonist diminished the sPLA₂-IIA inhibition. The obtained results show that APC effectively suppresses the up-regulated sPLA₂-IIA expression, which might contribute to the reported beneficial effects of APC in the treatment of severe inflammatory disorders.