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Ulcerative colitis (UC) is an unknown-cause inflammatory disease of colorectum. At present, there are no specific therapeutic drugs. We found that rosmarinic acid (RA) can significantly improve UC and further explored the relevant cellular and molecular mechanisms. Firstly, using F4/80 as marker for mouse macrophages, we found there were large numbers of macrophages infiltrating into colonic tissue of dextran sulfate sodium (DSS)-induced mice UC model. Meanwhile, RA markedly improved weight loss, diarrhea, hematochezia and colonic inflammation in mice with DSS treatment. Further, RA changed macrophage polarization in mouse colon, showing that classical activation (M1) phenotype decreased, alternative activation (M2) phenotype increased, and M1/M2 ratio reversed by Real-time PCR. In vitro, we cultured the peripheral blood macrophages (PBM) and found that RA inhibited PBM M1 polarization and favored M2 polarization directly. Heme oxygenase-1 (HO-1) mediated the anti-inflammatory effect of RA. RA induced HO-1 expression in PBM, and the HO-1 inhibitor, zinc protoporphyrin, blunted the inhibitory effect of RA on lipopolysaccharide (LPS)-induced nuclear factor-kappa B (NF-κB) translocation and M1 polarization. In addition, blocking NF-κB signal has no effect on the role of RA. In conclusion, RA protects against UC by regulating macrophage polarization depending on HO-1. These data suggest that reversing macrophage polarization can be used as a strategy for UC treatment and RA is an effective drug to cure UC by regulating macrophage polarization.