Cyclic nucleotides mediate transient as well as plastic cellular responses. The most ultimate response is cell death. In the present study, we propose that an increase of intracellular cyclic guanosine monophosphate (cGMP) for at least 1h promotes cell death in the murine microglial cell line, BV-2 cells, as well as in primary murine microglia. Cells were exposed to ammonium, the guanylyl cyclase inhibitor, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), and to the membrane-permeable cGMP analogue, 8-Bromo-cGMP (8-Br-cGMP), respectively. Cell death was estimated using DAPI labelling and annexin-V labelling of exposed phosphatidylserine, and cGMP level was quantified by an immunoassay. Ammonium not only increased the number of apoptotic cells but also promoted a moderate increase in intracellular cGMP. Addition of ODQ suppressed ammonium-induced apoptosis. Furthermore, we found that 8-Br-cGMP significantly increased the number of BV-2 cells and primary microglia, respectively, containing nuclei with condensed chromatin accumulated at the nuclear periphery. Similarly, cells exposed to 8-Br-cGMP showed significantly more cells with exposed phosphatidylserine compared to control cells. Thus, according to the nuclear structure as well as to changes in the plasma membrane, chronic elevation of cGMP induces apoptosis in microglia.