AbstractActivation of the 40‐kDa low‐affinity receptor for IgG (FcγRIIa, CD32) leads to tyrosine phosphorylation, increase of cytosolic free calcium concentration ([Ca2+]i), and production of superoxide anions (O2−) in neutrophils (PMN). It has been established that protein tyrosine kinases (PTK) and phosphatases (PTP) are essential for the regulation of intracellular signaling. CD45 is a type I receptor‐type protein tyrosine phosphatase (RPTP) with two PTP domains. Recently it has been demonstrated that co‐cross‐linking of CD45 modulates the signal transduction pathway of FcγRIIa in PMN. In contrast, the functional characteristics of CD148 (HPTPη/DEP‐1), a new RPTP with only one PTP domain, is unknown. CD148 is expressed on PMN in slightly lower density than CD45, and in higher density than on lymphocytes. [Ca2+]i measured with fluo‐3‐loaded PMN by flow cytometry and O2− production determined by lucigenin‐dependent chemiluminescence were inhibited by co‐cross‐linking of CD45 with FcγRIIa in comparison to isotype control monoclonal antibody (mAb). In contrast, preincubation with CD148 mAb 143‐41 abolished O2− generation, but did not inhibit [Ca2+]i rise. In summary, both clustered human RPTP, CD45 and CD148, inhibit FcγRIIa‐induced O2− production in PMN, but they differ in regulation of [Ca2+]i. Therefore, it is suggested that co‐cross‐linking of FcγRII with CD45 and CD148 leads to dephosphorylation of different substrates. These distinct functional capacities may be important for differential regulation of FcγR signaling by currently unknown ligands.