Pentoxifylline and the two analogues HWA138 and HWA448, at concentrations exceeding 60 micrograms/ml, inhibited malaria antigen or lipopolysaccharide (LPS) induced TNF-alpha and IL-1 alpha secretion, but not IL-6 secretion, from human peripheral blood mononuclear cells in vitro. HWA448 had lower inhibitory activity in vitro than pentoxifylline and HWA138. A small enhancement of cytokine secretion was induced by pentoxifylline and the two analogues at low concentrations. The drugs did not affect cell viability. Pentoxifylline, HWA138 and HWA448 also inhibited LPS induced TNF production in vivo in female CF1xBalb/c mice. The drugs were inhibitory at 0.5-1 mg per mouse when mixed with LPS, and 1 mg per mouse of the drugs was inhibitory when injected 1 h before LPS challenge. HWA448 had similar inhibitory activities in vivo compared to pentoxifylline and HWA138, possibly because of the longer serum half-life of HWA448. The pentoxifylline analogues may have lower toxicity than pentoxifylline itself and may therefore be useful in future treatment of diseases induced by endotoxic substances.