The human cytoplasmic protein tyrosine phosphatase (HCPTP) has been identified as a potential target for inhibition in order to downregulate metastatic transformation in several human epithelial cancers such as breast, prostate and colon cancer. Docking with two scoring functions on both isoforms of HCPTP was employed as an initial virtual screen to identify potential inhibitors. Compounds identified as potential inhibitors via this in silico screen were subjected to kinetic analysis in order to validate their selection as improved inhibitors. Eleven compounds with IC50's of less than 100 microM were identified in a single concentration screen. Five of these compounds were determined to have an IC50 of less than 10 microM; however, all but one of these compounds inhibited via non-specific aggregation. The validated effective inhibitor, which is based on a naphthyl sulfonic acid, strongly resembles a previously synthesized rationally designed azaindole phosphonic acid. This similarity suggests subsequent inhibitor optimization based on this scaffold may generate effective inhibitors of HCPTP. The structural elements of the computationally identified inhibitors are discussed to analyze the combined use of rational design and virtual screening to reduce false negatives in the identification of multiple strong inhibitors of HCPTP.