The capacity of human peripheral blood mononuclear cells and monocytes to generate nitrites, spontaneously or in response to Interleukin-4 was evaluated in vitro. Peripheral blood mononuclear cells and monocytes were found to release significant amounts of nitrites after 8 to 12 days in culture. This spontaneous production of nitrites was inhibited in the presence of 1 mM NG monomethyl-L-arginine, suggesting that this process was dependent upon the L-arginine metabolism. The present data also indicated that addition of Interleukin-4 generally resulted in an increased nitrite production, that was potentiated by IFN-gamma, inactive alone. The response of human monocytes to Interleukin-4 was more heterogenous than that observed with unfractionated peripheral blood mononuclear cells. These results suggest that cell/cell interactions could play an important role in the activation of the nitric oxide synthase pathway in human.