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 alpha(M)beta(1) (a direct binding) or alpha(V)beta(3) (an indirect binding mediated through intermediary plasma proteins). We studied the binding of factor H to platelets and to integrin alpha(IIb)beta(3) (glycoprotein IIb-IIIa), the most abundant integrin on platelets. We measured binding of purified factor H to platelets or heterologous cells expressing recombinant alpha(IIb)beta(3) using flow cytometry. We also measured binding of factor H to alpha(IIb)beta(3) in cell free systems using either surface plasmon resonance or enzyme-linked immunosorbent assay. We found that factor H directly binds to alpha(IIb)beta(3) and this binding has a dissociation constant (Kd) of 131 +/- 60.9 nM and is not dependent on active conformation of alpha(IIb)beta(3) or on the presence of cations. Considering the high affinity of this interaction, the abundance of alpha(IIb)beta(3) integrin on platelets, and the high concentration of factor H in plasma, alpha(IIb)beta(3) 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 alpha(IIb)beta(3) and perhaps involves other binding sites for factor H on platelets.