A series of naphthalenebis(difluoromethylenephosphonates) were prepared and compared to their monosubstituted counterparts as inhibitors of the protein phosphatases, PTP1B, CD45 and PP2A. In general, the bissubstituted compounds were better inhibitors than the mono derivatives and some of these are among the most potent, nonpeptidyl inhibitors of protein tyrosine phosphatases, PTP1B and CD45, reported to date.