The glycoprotein (Gp) Ib/IX complex contains three transmembranous leucine-rich repeat polypeptides (GpIbalpha, GpIbbeta, and GpIX) that form the platelet von Willebrand factor (vWF) receptor. GpIb/IX functions to effect platelet adhesion, activation, and aggregation under conditions of high shear stress. GpIb/IX is expressed late in the ontogeny of megakaryocytes, the precursor cell that releases platelets when it reaches its terminal stage of differentiation. Because signal pathways can be reused at different stages of development by integration with different effector pathways and because cellular adhesion through other receptor families often modulates cell growth, the hypothesis that GpIb/IX regulates cell growth was investigated. The surface expression of recombinant GpIbalpha decreases the proliferation of transduced CHO cells. GpIbalpha causes growth arrest in the G1 phase of the cell cycle associated with the induction of the cyclin-dependent kinase inhibitor p21. G1 arrest induced by recombinant GpIbalpha in heterologous cells requires signaling through the 14-3-3zeta binding domain of GpIbalpha and is partially dependent on its engagement by the extracellular ligand vWF. Growth arrest induced by the expression of recombinant GpIb/IX is followed by apoptosis of the transduced cells. The endogenous expression of GpIbalpha in human hematopoietic cells is associated with decreased proliferation. These results suggest that the expression of the GpIb/IX complex regulates megakaryocyte growth.