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This study investigated the anti-inflammatory effects and possible underlying mechanisms of Salvia miltiorrhiza polysaccharides (SMP) in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. The cytotoxicity of SMP was detected by the MTT method. The morphological change of RAW264.7 was observed by Diff-Quik staining. Enzyme-linked immunosorbent assay was used to evaluate the production of cytokines in LPS-induced RAW264.7 cells. The nitric oxide (NO) kit assay detected the NO release from LPS-induced RAW264.7 cells. Real-time polymerase chain reaction was used to detect the transcriptions of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), inducible NO synthase (iNOS), and cyclooxygenase (COX)-2 in LPS-induced RAW264.7 cells. The protein expression of nuclear NF-κB was measured by Western blot. The results showed that the safe medication range of SMP was less than 3 mg/mL. Compared with the LPS model group, SMP (2, 1, and 0.5 mg/mL) improved the degree of cell deformation and reduced the amount of pseudopodia, and statistically reduced the secretions of cytokines in cells induced by LPS (P 0.01) at different time points. SMP significantly inhibited the mRNA transcriptions of TNF-α, IL-6, iNOS, and COX-2 and the protein expressions of NF-κB, p-p65, and p-IκBa. In conclusion, this study preliminarily proved the protective effect of SMP on LPS-induced RAW264.7 macrophage. Its mechanism might be related to inhibition of NF-κB signal pathway and the gene expressions and secretion of cytokines.