Several Protein Tyrosine Phosphatases (PTPs) have been implicated in the control of Growth Hormone Receptor (GHR) signaling, but none have been shown to affect growth in vivo. We have applied a battery of molecular and cellular approaches to test a family-wide panel of PTPs for interference with GHR signaling. Among the subset of PTPs that showed activity in multiple readouts we selected PTP-H1/PTPN3 for further in vivo studies and found that mice lacking the PTP-H1 catalytic domain show significantly enhanced growth over their wild-type littermates. In addition, PTP-H1 mutant animals had enhanced plasma and liver mRNA expression of Insulin-like Growth Factor-1 (IGF-1), as well as increased bone density and mineral content. These observations point to a controlling role for PTP-H1 in modulating GHR signaling and systemic growth through IGF-1 secretion.