Human macrophages express oestrogen receptors and are therefore competent to respond to the hormone present in their microenvironment, which is implicated in sexual dimorphism observed in several immune and autoimmune phenomena. An earlier study from this laboratory demonstrated 17beta-oestradiol (E2) induced apoptosis in macrophages derived from human peripheral blood monocytes and THP-1 acute monocytic leukaemia cell line when Bcl-2 was down-regulated; however, the involvement of E2 receptor subtypes in the modulation of death pathways in these cells remain unknown. Using macrophages derived from THP-1 human acute monocytic leukaemia cells as a model, we demonstrate that plasma membrane associated oestrogen receptor (ER) -alpha participate in E2 induced Bcl-2 increase, through activation of the mitogen activated protein kinase (MAPK) pathway whereas cytosolic ER-beta transmits signals for the pro-apoptotic event of Bax translocation. The mechanistic basis of Bax translocation comprised of ER-beta mediated increase in intracellular pH, facilitated by activation of the Na(+)-H(+) exchanger. Intracellular alkalinization accompanied by concomitant Bcl-2 increase and Bax migration does not cause cellular apoptosis; however, siRNA mediated down-regulation of ER-alpha during E2 exposure leads to inhibition of Bcl-2 increase and consequently apoptosis due to the unopposed action of mitochondrial Bax. In summary, this study underscores the importance of integrative signalling modality from multiple oestrogen receptor pools in modulating oestrogen effects on human monocyte-derived macrophage apoptotic signalling pathway, which opens new vistas to explore the use of selective oestrogen receptor modulators in apoptosis-based therapies.