We have investigated the effects of ketamine on nitric oxide produced by activated macrophages using a murine macrophage-like cell line, J774. Cells were incubated for 18 h under stimulation with lipopolysaccharide and interferon-gamma or lipoteichoic acid and interferon-gamma, with various concentrations of ketamine (6-600 mumol litre-1). Nitric oxide production was assessed by measuring nitrite, a stable by-product of nitric oxide breakdown, in the medium. Other N-methyl-D-aspartate receptor antagonists, MK-801 (150 mumol litre-1) and dextromethorphan (150 mumol litre-1) were also tested. In addition, we studied the effects of ketamine on production of tumour necrosis factor-alpha by activated macrophages. Ketamine inhibited nitrite production dose-dependently with both lipopolysaccharide- and lipoteichoic acid-activated macrophages by up to approximately 65% at the highest ketamine concentration (600 mumol litre-1). Neither MK-801 nor dextromethorphan had an inhibitory effect. Ketamine also suppressed production of tumour necrosis factor-alpha. The data show that ketamine inhibited nitric oxide production by activated macrophages probably, in part, via inhibition of production of tumour necrosis factor-alpha, an autocrine stimulatory factor for nitric oxide production, but not via the NMDA receptor pathway, which is involved in neuronal nitric oxide production.