Protein tyrosine phosphatases (PTPs) cooperate with protein tyrosine kinases to regulate signal transduction pathways. Genome-wide surveys cataloging protein tyrosine phosphatases in humans have recently been carried out. Here, we present a bioinformatics analysis of protein tyrosine phosphatases in the human genome to examine their domain architecture, alternative splicing and pseudogenes. We present evidence that alternative transcripts exist for 25 out of 35 PTPs analyzed. These alternative transcripts include novel exons; skipped exons as well as cryptic donor/acceptor splice sites. We discovered a novel isoform of PTPN18 based on analysis of expressed sequence tags (ESTs). The deletion of 4 exons in the catalytic domain of the novel isoform may alter the enzymatic activity toward its substrates. We were able to experimentally validate 2 of our novel isoform predictions through RT-PCR. Finally, a user-friendly web-based resource that consolidates the gene and protein annotations for all human protein tyrosine phosphatases has been developed and is freely available at http//ptpr.ibioinformatics.org.