This study was designed to investigate whether anti-IgE-induced or ionophore A23187-induced histamine release from human basophils is regulated by exogenous nitric oxide (NO), and to assess some similarities between the effect of NO on basophils and that on rat peritoneal mast cells (RPMC). The NO donor, sodium nitroprusside (SNP), inhibited A23187-induced histamine release from crude human basophils and crude RPMC in a dose-dependent fashion. This downregulation was still observed when SNP was washed out just before the cell stimulation, indicating that the effect of SNP was irreversible. The downregulation disappeared in both purified cell populations after the removal of contaminating cells. However, when purified cells were preincubated with SNP in the presence of 5 mM N-acetylcysteine (NAC), increasing the bioavailability of NO, the downregulation was recovered. The presence of NAC significantly augmented the downregulation of SNP on A23187-induced histamine release from both crude cell populations. In contrast, SNP had no effect on anti-IgE-induced histamine release from either crude or purified basophil preparation in the absence of NAC, and SNP plus NAC inhibited anti-IgE-induced histamine release from both cell preparations. The same results were obtained with crude and purified RPMC preparations under the same conditions. These results show that SNP similarly downregulated exocytosis of basophils and RPMC, and acquired the potent effect in the presence of NAC, indicating that exogenous NO plays a part in the regulation of basophil and mast cell activation.