Platelet transfusions from donors matched for cross-reactive antigens have been shown to be effective in providing hemostasis in alloimmunized thrombocytopenic patients. A significant number of these transfusions, however, fail to provide posttransfusion platelet recoveries. We investigated incompatibility in the Bw4/bw6 system as a possible explanation for these failures. The Bw4/Bw6 system is a biallelic antigen system closely associated with HLA-B. HLA-B locus antigens that are cross-reactive frequently differ in their Bw4/Bw6 specificity. Posttransfusion platelet recoveries from 21 alloimmunized thrombocytopenic patients homozygous for Bw4 or Bw6 and transfused with both Bw4/Bw6 compatible and incompatible platelets were analyzed. The mean 1-hr posttransfusion recovery was 84% following Bw4/Bw6-compatible platelets versus 52% with Bw4/Bw6-incompatible platelets (p less than 0.02). Twenty-four hours following transfusion, mean recoveries were 44% and 24%, respectively, (p less than 0.01). A subgroup of 8 patients (38%) was identified who had markedly lower responses following Bw4/Bw6- incompatible transfusions as compared to Bw4/Bw6-compatible transfusions (mean recoveries: 1 hr--compatible 100%, incompatible 27%, p less than 0.001; 24 hr--compatible 45%, incompatible 7%, p less than 0.01). These data suggest that the Bw4/Bw6 antigen system has clinical significance for some patients requiring platelet transfusion therapy and, when appropriate, should be considered in the selection of donors.