One of the major events following phagocyte activation is production of reactive oxygen species (ROS) by NADPH-oxidase 2 (NOX2). This process critically depends on store-operated Ca²⁺ entry (SOCE) mediated by ORAI Ca²⁺ channel family. However, the molecular mechanism by which the ORAI channels regulate NOX2 activity is not fully understood. Our findings indicate that oxidation suppresses SOCE by inhibiting ORAI1 and ORAI2 but not ORAI3 channels, pointing to a protective role for ORAI3 against oxidative stress. Because human monocytes express relatively high amounts of both NOX2 and ORAI3 we examined the interplay between these two proteins and their co-regulation. Using electron paramagnetic resonance (EPR) and fluorescent ROS measurements, we show that human monocytes produce significant amounts of superoxide (O₂^•-) upon activation of SOCE by thapsigargin (Tg) or bacterial fMLP. This O₂^•- production was completely abolished under Ca²⁺-free conditions or in presence of 2-APB, suggesting a major role for SOCE in the regulation of NOX2. Furthermore, using Ca²⁺ imaging we found that Tg or fMLP triggered SOCE in monocytes is less inhibited by oxidation in comparison with other leukocytes. This increased redox resistance was reversed by small interfering RNA-based knockdown of ORAI3; resulting again in stronger indirect feedback inhibition of NOX2 activity by H₂O₂ induced inhibition of SOCE. Expression of ORAI3 channels thus leads to reduced redox sensitivity of SOCE and thereby indirectly maintains a prolonged NOX2 activation.