Extracts of Spondias mombin L. (Anacardiacea) is used in the traditional medicine of Africa and Latin America to treat many inflammatory conditions, with repeated claims of efficacy. However, there are no scientific data yet to support these claims and the mechanism through which the extract may be acting is still unknown. This study was undertaken to investigate the effects of the methanolic extract of the leaf of S. mombin (SM) on inflammation and to uncover some of the possible mechanisms that could explain any observed changes. The anti-inflammatory activity of the extract was investigated in Wistar rats using intraplantar injection of carrageenan as an in vivo model of inflammation. The effect of oral supplementation of the SM extract on tumor necrosis factor (TNF)-α levels after an intraperitoneal lipopolysaccharide (LPS; 1 mg/kg) challenge was investigated in mice. The effect of SM on TNF-α and inducible nitric oxide (iNO) production by LPS-stimulated bone marrow-derived macrophages (BM-MØ) was also investigated in vitro. BM-MØ were preincubated for 2 h with SM (0-100 μg/ml), activated with LPS, and then TNF-α and NO production measured in the cell-free conditioned culture supernatant after 24 h of incubation. The study showed that pre-treatment of rats with the SM extract (at 100, 200, and 400 mg/kg, per os) caused a significant dose-related inhibition of carrageenan-induced paw edema over a 4-h period. In treated mice, LPS-inducible (systemic) TNF-α levels were found to be significantly lower as a result of their receiving the SM extract. In vitro, SM treatment caused a dose-dependent decrease in LPS-inducible TNF-α and NO production by BM-MØ compared to the effects of treatment of the cells with LPS alone. Taken together, the results of these studies suggest that supplementation with SM extract can alleviate inflammatory responses and that this could possibly be via a suppression of the production of pro-inflammatory mediators and cytokines such as TNF-α and iNO.