Abstract: In this study, in vitro experiments were conducted to investigate that sinomenine inhibits the macrophage classic activation by up-regulating the expression of paired immunoglobulin-like receptor B (PIR-B). A macrophage model with classic activation was established by lipopolysaccharide and interferon-gamma co-stimulation. Real-time fluorescence reverse transcription-polymerase chain reaction was executed for evaluating the PIR-B gene expression, and Western blot for PIR-B protein expression, in macrophages, respectively. The tumor necrosis factor α and interleukin 8 in cell culture supernatant were measured by enzyme-linked immunosorbent assay. The flow cytometry was utilized to detect M1 macrophages. The PIR-B expression in situ was observed by laser scanning confocal microscope. The results showed that sinomenine significantly increased the expression of PIR-B, markedly reduced the percentage of M1 macrophages, and decreased the levels of tumor necrosis factor α and interleukin 8 in the culture supernatant. The above results indicated that sinomenine can significantly inhibit the macrophage classic activation, and its mechanism may be related to the increase of PIR-B expression in macrophages. This pharmacological effect helps explain the pharmacodynamic mechanism of sinomenine in treating rheumatoid arthritis.