Pinosylvin is known to have anti-inflammatory activity in endothelial cells. In this study, we found that pinosylvin had a pro-apoptotic activity in lipopolysaccharide (LPS)-preconditioned leukocytes. This finding suggests that pinosylvin has an effect on the resolution of inflammation. To understand the detailed mechanism, we examined if pinosylvin enhances cyclooxygenase (COX) or lipoxygenase (LOX) activity in THP-1 and U937 cells. LOX activity was found to be markedly increased by pinosylvin, whereas COX activity was not altered. Furthermore, we found that pinosylvin enhanced both levels of ALOX 15 mRNA and protein, implying that LOX activity, elevated by pinosylvin, is attributed to upregulation of ALOX 15 expression. From this cell signaling study, pinosylvin appeared to promote phosphorylations of ERK and JNK. ERK or JNK inhibitors were found to attenuate ALOX 15 expression and LPS-induced apoptosis promoted by pinosylvin. In conclusion, pinosylvin enhances the apoptosis of LPS-preconditioned leukocytes by up-regulating ALOX 15 expression through ERK and JNK. These findings suggest that pinosylvin may induce the resolution of inflammation.