Rikko-san (RKS) and its ingredients were investigated for their activity to stimulate prostaglandin E2 (PGE2) production by unstimulated and lipopolysaccharide (LPS)-stimulated mouse macrophage-like Raw 264.7 cells. LPS significantly stimulated the production and extracellular secretion of PGE2 by Raw 264.7 cells. RKS dose-dependently modified the LPS-stimulated PGE2 production. A lower concentration (0.04-0.4 mg/ml) of RKS stimulated PGE2 production without or with LPS, whereas a higher concentration (4 mg/ml) of RKS inhibited the LPS-stimulated PGE2 production, suggesting the presence of both stimulator(s) and inhibitor(s) for PGE2 production. The inhibitory effect of a higher concentration of RKS was slightly neutralized by supplementation of exogenous arachidonic acid. Among five RKS ingredients, Kanzo inhibited the LPS-stimulated PGE2 production to the greatest extent, whereas other ingredients (Shoma, Ryutan, Saishin, Bofu) stimulated PGE2 production. Western blot analysis demonstrated that RKS and all its ingredients enhanced the intracellular concentration of cyclooxygenase-2, whereas RKS did not significantly affect the phospholipase A2 protein level. The present study demonstrates that the concentration-dependent effect of RKS on the PGE2 production by macrophage cannot be explained only by the expression levels of cyclooxygenase-2 or phospholipase A2.