The interaction of phosphatidylserine (PS), exposed on the surface of apoptotic cells and with its specific receptor (PtdSerR) expressed by microglia, is a crucial event in the recognition and clearance of apoptotic neurons. Here, we extend our previous studies in which PS-liposomes mimicking apoptotic cells were used to investigate the functional role of PS-PtdSerR interactions on microglial functional state. Purified rat microglial cells were either incubated with PC12 cells maintained in complete medium (healthy), exposed to staurosporine or serum deprivation (apoptotic), or treated with hydrogen peroxide (necrotic). After 24 hours, supernatants from co-cultures and single cell type cultures were analyzed for nitric oxide (NO), tumor necrosis factor-alpha (TNF-alpha), interleukin-10 (IL-10), prostaglandin E2 (PGE2), transforming growth factor-beta1 (TGF-beta1), and nerve growth factor (NGF). When lipopolysaccharide (LPS)-activated microglia was cultured with apoptotic PC12 cells, NO and TNF-alpha levels significantly decreased, IL-10 was not affected, and PGE2 levels were substantially increased. In addition, TGF-beta and NGF syntheses increased when resting microglia was cultured with apoptotic but not healthy or necrotic PC12 cells. We proposed that upon interaction with PS-expressing apoptotic neurons, microglia no longer act as a promoter of the inflammatory cascade and that the specific microglial functional state induced by PS-PtdSerR may be relevant for the final outcome of neurodegenerative diseases.