Two different types of FcRs for IgG are constitutively expressed on the surface of human neutrophils, namely, FcγRIIA (CD32a) and FcγRIIIB (CD16b). Unlike FcγRIIA, FcγRIIIb is GPI anchored to the cell membrane and its signal transduction is still ambiguous. To further understand the signal transduction of CD16b, we compared neutrophil cytokine expression and apoptosis by the cross-linking of CD32a and CD16b respectively. We found that both CD32a and CD16b crosslinking can activate neutrophils, but did not exactly share cytokine expression profiles. On the other hand, CD16b cross-linking retarded neutrophil apoptosis while CD32a promoted it. By interrupting the lipid raft with methyl-β-cyclodextrin (MβCD) and inhibiting the ITAM-SYK pathway with an SYK inhibitor (piceatannol), we found reduced apoptosis was at least partially mediated by lipid raft structure, but not the ITAM-SYK pathway. Additionally, CD16b but not CD32a cross-linking triggered SHP-2 phosphorylation and led to its translocation into lipid rafts. SHP-2 phosphorylation and translocation were inhibited by MβCD. Moreover, pre-inhibition of SHP-2 by a specific inhibitor (SHP099) converted IL-10 and SOCS3 expression level and promoted neutrophil apoptosis after CD16b crosslinking. In conclusion, these results, for the first time, collectively indicate that SHP-2 is activated by CD16b crosslinking in neutrophils and functions as a component of the raft-mediated signaling pathway.