Granulomatous inflammation is associated with a variety of important pathologic conditions. Osteopontin (OPN), a ligand for the alpha v beta 3 integrin, is a secreted glycoprotein with a glycine-arginine-glycine-aspartate-serine cell-binding domain. In this study, we examined expression of OPN in 22 cases of granulomatous inflammation including cases of sarcoidosis, granulomatous temporal arteritis, histoplasmosis, rheumatoid nodule, granuloma annulare, erythema nodosum, granulomatous gastritis, foreign body giant-cell granulomatous reactions, and lipogranulomas. Strong expression of OPN mRNA and protein was seen in the epithelioid histiocytes and multinucleate histiocytic giant cells in granulomas by in situ hybridization and immunostaining. OPN may play an important role in granulomatous inflammation through the regulation of processes such as histiocyte migration, cell adhesion, and cellular functions including phagocytosis.