Statins are known to be anti-inflammatory, but the mechanism remains poorly understood. Here, we show that macrophages, either treated with statin in vitro or from statin-treated mice, have reduced cholesterol levels and higher expression of , a H3K27me3 demethylase. We provide evidence that lowering cholesterol levels in macrophages suppresses the adenosine triphosphate (ATP) synthase in the inner mitochondrial membrane and changes the proton gradient in the mitochondria. This activates nuclear factor kappa-B (NF-κB) and expression, which removes the repressive marker H3K27me3. Accordingly, the epigenome is altered by the cholesterol reduction. When subsequently challenged by the inflammatory stimulus lipopolysaccharide (M1), macrophages, either treated with statins in vitro or isolated from statin-fed mice, express lower levels proinflammatory cytokines than controls, while augmenting anti-inflammatory expression. On the other hand, when macrophages are alternatively activated by IL-4 (M2), statins promote the expression of , , and . The enhanced expression is correlated with the statin-induced removal of H3K27me3 from these genes prior to activation. In addition, and its demethylase activity are necessary for cholesterol to modulate both M1 and M2 activation. We conclude that upregulation of is a key event for the anti-inflammatory function of statins on macrophages.