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There is an ongoing debate about possible advantages of the coadministration of caffeine with cyclooxygenase (COX) inhibitors in the treatment of pain. There are results suggesting interference by caffeine with COX expression and activity in rat immune cells. In the present study, we have used, therefore, human endotoxin-stimulated monocytes to investigate a possible influence of caffeine on indometacin-induced inhibition of prostaglandin E₂ (PGE₂) formation. Endotoxin caused a concentration- and time-dependent increase in immunoreactive PGE₂ that was dependent on CD14-mediated mechanisms. In order to investigate pharmacological inhibition of the COX activity, a submaximal concentration of 1 ng/ml endotoxin (4 h exposure time) was used. Indometacin caused a concentration-dependent inhibition of PGE₂ with an apparent IC₅₀ of 8.9 ± 1.4 × 10^–9 mol/l and an I_max of 1 x 10^–7 mol/l. Caffeine (5 × 10^–6 to 1.5 × 10^–4 mol/l) on its own produced no statistically significant effect on endotoxin-induced PGE₂ formation. In the presence of caffeine (5 × 10^–6 to 1.5 × 10^–4 mol/l), inhibition of PGE₂ biosynthesis by indometacin (1 × 10^–8 mol/l) was not significantly altered. These results show that, in human monocytes, caffeine, up to concentrations severalfold higher than those reached in patients, has no significant effect on endotoxin-induced PGE₂ formation nor on its inhibition by indometacin.