Sinomenine (SN), an immunnosuppressive compound derived from the Chinese medicinal plant Sinomenium acutum, has been used to treat autoimmune diseases effectively. Previous studies show SN can inhibit lymphocytes proliferation and macrophage production of pro-inflammatory factors. However, little is known about the mechanisms by which SN inhibits macrophage functions. In this study, we demonstrated that SN could inhibit the proliferation of murine macrophages RAW264.7 by inducing apoptosis in a dose- and time-dependent manner. We found activation of extracellular signal-regulated protein kinase (ERK) in SN-treated macrophages, and requirement for ERK activation in SN-induced apoptosis of macrophages. Contemporarily, the expression of p27/KIP1, proapoptotic factor Bax increased, and expression of Bcl-2 decreased, which might cooperate to induce apoptosis. Inhibiting ERK activation reduced the increased expression of p27 and Bax, but had no effect on the decreased expression of Bcl-2, suggesting the involvement of ERK activation in the SN-induced increased expression of p27 and Bax. These results demonstrated that SN could induce apoptosis of macrophages through activation of ERK, and ERK activation might partially involve in the increased expression of p27 and Bax in apoptotic macrophages. Therefore, induction of macrophage apoptosis through ERK activation may be one of mechanisms by which SN exhibits its immunosuppressive function.