Recent studies have postulated the contribution of nitric oxide (NO) released by the endothelium to the beneficial effects of estrogen. Despite a neuronal-type NO synthase (nNOS) described in neutrophils, less is known about the effect of estrogen in these cells. The aim of the present study was to analyze the expression of nNOS protein in human neutrophils under different estrogenic conditions. We first analyzed nNOS expression in neutrophils obtained from premenopausal women. During the first 2 days of the follicular phase (low circulating estrogen concentrations), nNOS expression in neutrophils was reduced with respect to that found in neutrophils obtained from the same donors during the ovulatory phase (high circulating estrogen concentrations). Moreover, the expression of nNOS protein in neutrophils obtained from postmenopausal women after transdermal estrogen therapy was markedly enhanced with respect to that observed before the treatment. In vitro incubation of neutrophils derived from men for 6 hours with 17&bgr;-estradiol (10−10to 10−8mol/L) upregulated the expression of nNOS protein. The 17&bgr;-estradiol receptor antagonists, tamoxifen (10−8mol/L) and ICI 182780 (10−8mol/L), inhibited the upregulation of nNOS protein induced by 17&bgr;-estradiol. The putative functional implication was denoted by a reduced expression of the CD18 antigen on the surface of 17&bgr;-estradiol–incubated neutrophils, which was accompanied by a decreased adhesive capacity. Both effects were prevented by an NO antagonist. In conclusion, the in vivo levels of circulating estrogen concentrations seem to be associated with the level of nNOS protein expression in neutrophils from women. Moreover, low doses of 17&bgr;-estradiol upregulate nNOS protein expression in neutrophils from men. The increased ability of 17&bgr;-estradiol–incubated neutrophils derived from men to produce NO reduced their adhesive properties.