Human neutrophil IgA receptors (Fc alpha R) trigger phagocytosis of IgA opsonized particles and activate the NADPH oxidase complex ultimately leading to pathogen destruction. Signal transduction events triggered by Fc alpha R have not been investigated in the context of NADPH oxidase activation. In this study, we show that crosslinking Fc alpha R triggers the release of Ca2+ from an intracellular store that was unchanged by the addition of extracellular EGTA. This was in contrast to the thapsigargin-triggered Ca2+ signal, which activates store-operated Ca2+ entry pathways (SOCP) and is sensitive to extracellular EGTA. Buffering extracellular Ca2+ with EGTA had no effect on Fc alpha R-triggered NADPH oxidase activation, suggesting that SOCP was not required for activation by FcaR EGTA inhibited thapsigargin-triggered NADPH oxidase activation but had no effect on PMA-triggered responses, The intracellular Ca2+ chelator BAPTA caused dose-dependent inhibition of both Fc alpha R-triggered and thapsigargin-triggered NADPH oxidase activation but had no effect on PMA-triggered responses. Our data demonstrate that Fc alpha R-triggered NADPH oxidase activation is dependent on the release of Ca2+ from an intracellular store, but is independent Of SOCP.