Receptor protein-tyrosine phosphatase alpha, RPTP alpha, is a typical transmembrane protein-tyrosine phosphatase (PTP) with two cytoplasmic catalytic domains. RPTP alpha became strongly phosphorylated on tyrosine upon treatment of cells with the PTP inhibitor pervanadate. Surprisingly, mutation of the catalytic site Cys in the membrane distal PTP domain (D2), but not of the membrane proximal PTP domain (D1) that harbors the majority of the PTP activity, almost completely abolished pervanadate-induced tyrosine phosphorylation. Pervanadate-induced RPTP alpha tyrosine phosphorylation was not restricted to Tyr789, a known phosphorylation site. Cotransfection of wildtype RPTP alpha did not potentiate tyrosine phosphorylation of inactive RPTP alpha-C433SC723S, suggesting that RPTP alpha-mediated activation of kinase(s) does not underlie the observed effects. Mapping experiments indicated that pervanadate-induced tyrosine phosphorylation sites localized predominantly, but not exclusively, to the C-terminus. Our results demonstrate that RPTP alpha-D2 played a role in pervanadate-induced tyrosine phosphorylation of RPTP alpha, which may suggest that RPTP alpha-D2 is involved in protein-protein interactions.