The relief of nasal congestion with the antihistamine fexofenadine in seasonal allergic rhinitis is thought to be due to its additional anti-inflammatory properties. The objective of this study was to evaluate the in vitro effects of fexofenadine on stimulated arachidonic acid metabolism. Human monocytes, isolated from blood and donated by 5 healthy volunteers, were either incubated for 20 h with 10 µg/ml lipopolysaccharide, with and without fexofenadine (10<sup>–8</sup>–10<sup>–3</sup> mol/l, n = 8–19), or were incubated for 20 h, with and without fexofenadine, and then stimulated with 0.5 mg/ml zymosan for 2 h. Leukotriene B<sub>4</sub> (LTB<sub>4</sub>), LTC<sub>4</sub>, LTD<sub>4</sub> and LTE<sub>4</sub>, prostaglandin E<sub>2</sub> (PGE<sub>2</sub>) and F<sub>2</sub>α(PGF<sub>2</sub>α) production was determined by enzyme immunoassay. Zymosan-stimulated production of LTC<sub>4</sub>, LTD<sub>4</sub> and LTE<sub>4</sub> was significantly inhibited by clinically relevant concentrations of fexofenadine HCl: 10<sup>–7</sup>mol/l (22% inhibition vs. control, p = 0.008) and 10<sup>–6</sup> mol/l (24% inhibition vs. control, p = 0.020). Higher concentrations of fexofenadine (10<sup>–4</sup> and 10<sup>–3</sup> mol/l) inhibited LTB<sub>4</sub> generation. Lipopolysaccharide-stimulated production of PGE<sub>2</sub> was significantly inhibited by fexofenadine HCI 10<sup>–6</sup> mol/l (26% inhibition, p = 0.035) and 10<sup>–5</sup> mol/l (40% inhibition, p = 0.001). Higher concentrations of fexofenadine HCI (10<sup>–4</sup> and 10<sup>–3</sup> mol/l) significantly inhibited PGF<sub>2</sub>α production by 50% (p = 0.026) and 63% (p = 0.001), respectively. Fexofenadine, at both clinically relevant and higher concentrations, inhibits LTC<sub>4</sub>, LTD<sub>4</sub>, LTE<sub>4</sub> and PGE<sub>2</sub> in cultured human monocytes. These additional anti-inflammatory properties may underlie the relief of nasal congestion observed in clinical studies.