A macrophage cell line (J774), activated with interferon-gamma and endotoxin to express the inducible form of NO synthase (iNOS), immediately inhibited the cellular respiration of co-incubated L-929 fibroblasts or non-activated J774 macrophages. The inhibition was potent, rapid and reversible when the NO was removed by adding oxyhaemoglobin or by inhibiting iNOS. Exogenously added NO also rapidly and reversibly inhibited cellular respiration over the same range of NO concentrations. This inhibition was competitive with oxygen and due to direct inhibition of cytochrome oxidase. Thus, NO generated by one cell can regulate the respiration of adjacent cells, supporting the hypothesis that NO may be a physiological and/or pathological regulator of cellular respiration, via its inhibition of cytochrome oxidase.