Macrophages express several lysosomal cysteine proteases such as cathepsins and legumain. In this study, we assessed the expression, activity and secretion of legumain in cellular models of monocytes/macrophages. Macrophages were derived from M-CSF- or GM-CSF/IFNγ-stimulated human primary monocytes (M2 and M1, respectively), PMA-treated human THP-1 cells, or murine RAW264.7 macrophages. In both primary monocytes and THP-1 cells, monocyte-to-macrophage differentiation caused highly increased cellular expression and activity of legumain. Also, secretion of legumain from macrophages, but not from monocytes, was observed. Notably, M2 macrophages expressed significantly higher levels of active legumain than M1 macrophages, which are not previously reported. Legumain mRNA has been shown to be down-regulated in monocytes isolated from patients treated with the HMG-CoA reductase inhibitor atorvastatin. Interestingly, in our study, the active legumain produced by M2 macrophages was found to be inhibited by atorvastatin, which was reflected in aberrant cellular expression and processing.