To clarify the role of tumor necrosis factor (TNF)-alpha on osteoblast functions in the presence of metal particles, two human osteoblast-like cell lines (MG-63 and SaOS-2) were cultured with TNF-alpha in the presence or absence of titanium particles in vitro. A combination of TNF-alpha and titanium particles showed additive effects on inhibition of cell proliferation and alkaline phosphatase production. On the other hand, production of interleukin-6, which is well known to induce osteoclastogenesis and to directly stimulate bone resorption, was additively stimulated by the combination of TNF-alpha and titanium particles. These results suggest that the association of TNF-alpha and titanium particles may play an important role in the pathogenesis of periprosthetic osteolysis through two different pathways: a reduced periprosthetic bone formation due to inhibition of osteoblast proliferation and alkaline phosphatase production, and osteoblast-mediated activation of osteoclastic bone resorption as suggested by the enhancement of interleukin-6 production.