Background: Pentoxifylline (Trental) is a methylxanthine-derivative drug that has been used for more than twenty years in the treatment of peripheral vascular disease. Pentoxifylline is also a potent inhibitor of tumor necrosis factor-alpha (TNF-α) secretion, both in vitro and in vivo, and has demonstrated efficacy in the treatment of certain animal and human inflammatory diseases. Pentoxifylline has a potential therapeutic role in the treatment of aseptic loosening of total joint replacement components because it inhibits TNF-α secretion by particle-stimulated human peripheral blood monocytes. The purpose of our study was to determine whether the particle-stimulated secretion of TNF-α by peripheral blood monocytes was inhibited in volunteers who had received pentoxifylline orally. Methods: Human peripheral blood monocytes were harvested from eight healthy volunteers and were exposed to three different concentrations of titanium particles or to 500 ng/mL of lipopolysaccharide as a positive control. The same volunteers were then given pentoxifylline (400 mg, five times per day) for seven days. Their peripheral blood monocytes were again isolated and exposed to experimental conditions, and the TNF-α levels were measured. Results: The peripheral blood monocytes from all eight volunteers showed a significant reduction in TNF-α release following oral treatment with pentoxifylline. This reduction was observed at exposures of 107 and 106 titanium particles/mL and in the lipopolysaccharide-treated group, but not at 105 particles/mL. Conclusions: To our knowledge, this is the first study to demonstrate the ability of an oral drug to decrease the release of TNF-α from human peripheral blood monocytes exposed ex vivo to particle debris. TNF-α is involved in the pathogenesis of osteolysis and subsequent loosening of total joint arthroplasty components. The ability to suppress the release of TNF-α in patients with a total joint replacement may help to control osteolysis and to reduce the development of aseptic loosening. This effect could increase implant longevity and decrease the need for revision arthroplasty.