Wiskott-Aldrich syndrome (WAS) thrombocytopenia is frequently improved by splenectomy, although the mechanism of the thrombocytopenia and its resolution are unknown. Previous studies in two patients have shown that mean platelet volume, which is characteristically reduced in WAS, increased along with platelet count postsplenectomy. Additional studies in a limited number of patients have also demonstrated that platelet- associated immunoglobulin G (PAIgG) is elevated presplenectomy, but to date no postsplenectomy data have been reported. The present study was performed to more fully evaluate the effect of splenectomy on platelet volume and PAIgG in WAS. Before splenectomy, mean platelet volume was reduced but platelet size was broadly distributed with substantial overlap of the normal range. PAIgG was significantly elevated in 13 of 14 presplenectomy WAS patients (means = 78.9 fg per platelet) and fell to normal levels postoperatively (means = 4.0 fg per platelet). Platelet count and clinical status improved postsplenectomy, and mean platelet volume and platelet volume distribution returned to the normal range. WAS subjects who relapsed with recurrent thrombocytopenia redeveloped elevated PAIgG but maintained normal platelet size. The spleen appears to play a critical role in a process that may be immunologically mediated and results in reduced platelet size.