Factor H is a plasma protein that regulates activity of the alternative complement pathway in plasma and on cell surface. Binding of factor H to a cell surface protects that cell against complement-induced damage. Factor H binds to glycosoaminoglycans, surface-immobilized C3b, L selectin, and integrins such as α_Mβ₁ (a direct binding) or α_Vβ₃ (an indirect binding mediated through intermediary plasma proteins). We studied the binding of factor H to platelets and to integrin α_IIbβ₃ (glycoprotein IIb-IIIa), the most abundant integrin on platelets. We measured binding of purified factor H to platelets or heterologous cells expressing recombinant α_IIbβ₃ using flow cytometry. We also measured binding of factor H to α_IIbβ₃ in cell free systems using either surface plasmon resonance or enzyme-linked immunosorbent assay. We found that factor H directly binds to α_IIbβ₃ and this binding has a dissociation constant (Kd) of 131 ± 60.9 nM and is not dependent on active conformation of α_IIbβ₃ or on the presence of cations. Considering the high affinity of this interaction, the abundance of α_IIbβ₃ integrin on platelets, and the high concentration of factor H in plasma, α_IIbβ₃ provides a constitutive presence of factor H on platelets. Activation of platelets increases platelet-bound factor; however, this increase in binding of factor H cannot be explained by additional binding of factor H to α_IIbβ₃ and perhaps involves other binding sites for factor H on platelets.