Platelet refractoriness is the repeated failure to obtain satisfactory responses to platelet transfusions. It is mainly due to shortened platelet survival associated with non-immune clinical factors, such as infection and its treatment with antibiotics and antifungal drugs, disseminated intravascular coagulation (DIC) and splenomegaly. The main immune cause is HLA alloimmunization which occurs predominantly in females with a history of pregnancy. The incidence of alloimmune platelet refractoriness due to HLA antibodies has declined due to leucocyte reduction in blood components and more aggressive treatment for patients with haematological malignancies and other cancers. Responses to platelet transfusions should be carefully monitored. If platelet refractoriness occurs, a clinical assessment should be made for clinical factors associated with non-immune platelet consumption. If there are no obvious clinical factors present, an immune mechanism should be suspected and testing for HLA antibodies conducted. If HLA antibodies are detected, HLA-matched platelet transfusions should be used. There are a number of methods including computer algorithms to determine HLA compatibility and acceptable HLA mismatches. HLA-matched platelet transfusions are not indicated when serological testing has failed to detect HLA antibodies; further consideration should be given to the presence of non-immune clinical factors and testing for HPA antibodies. If there are improved responses to HLA-matched platelet transfusions, they should be continued. If there are poor responses to HLA-matched platelet transfusions, the reasons should be sought including HLA incompatibility which is most likely to occur in patients with unusual HLA types with few well-matched donors, non-immune platelet consumption, and HPA and ABO incompatibility. Further serological investigations including testing for HPA antibodies and/or platelet cross-matching may be used to differentiate between these possibilities. The management of patients with HLA and/or HPA alloimmunization and no compatible donors may be very difficult. The management of patients with non-immune platelet consumption is similarly problematic.