A novel protein-tyrosine phosphatase, PTPφ, was cloned from a murine macrophage cDNA library. As a result of alternative splicing, macrophage PTPφ mRNAs are predicted to encode two membrane-spanning molecules and a cytosolic enzyme with identical catalytic domains. The membrane-spanning forms differ in the juxtamembrane region, while a start codon downstream of this region is utilized in the translation of the putative cytosolic form. Expression of PTPφ mRNA is low and restricted to macrophage cell lines, macrophage-rich tissues, and brain, kidney, and heart. The mRNA in macrophages and heart is ∼2.8 kilobases (kb). However, a ∼5.5-kb transcript in brain and kidney indicates a fourth isoform encoding a large extracellular domain. The ∼5.5-kb PTPφ brain mRNA encodes the mouse homolog of GLEPP1, a recently reported glomerular epithelial protein. The level of expression of the mRNA encoding the cytosolic form was very low, and only the membrane-spanning proteins (43 and 47 kDa) could be detected in macrophages. Following addition of colony stimulating factor-1 to quiescent BAC1.2F5 macrophages, PTPφ mRNA and protein were down-regulated. The restricted expression of the shorter isoforms of PTPφ and their regulation by colony stimulating factor-1 in macrophages suggest that PTPφ may play a role in mononuclear phagocyte survival, proliferation, and/or differentiation.