In septic shock tumor necrosis factor (TNF) leads to increased nitric oxide (NO) production by induction of NO synthase. An inverse regulatory effect, the influence of NO on cytokine synthesis, has rarely been investigated. The present study assessed the influence of NO-releasing agents on TNF production from interleukin-1 alpha (IL-1 alpha)-stimulated human peripheral blood mononuclear cells (PBMC). 3-Morpholino-sydnonimine (SIN-1) enhanced IL-1 alpha-induced TNF synthesis to a maximum of 272% (mean of n = 5 donors), with 100% set as TNF production by stimulation with IL-1 alpha alone. This finding was confirmed using another NO-donor, i.e., sodium nitroprusside (SNP). The effect was specific for TNF compared to the uninfluenced synthesis of IL-1 beta. Kinetic analysis showed the most pronounced increase in TNF synthesis when SIN-1 was added during the first 60 min after IL-1 alpha addition. These data reveal an enhancing effect of NO on cytokine-induced TNF synthesis. It may contribute to the regulation of TNF synthesis in pathological processes such as microbicidal activity, tumor cell lysis or endothelium-mediated hypotension.