In recent years clinical factors have largely surpassed alloimmunization as the predominant cause of platelet refractoriness. This makes it necessary to properly identify and weigh the non-immune factors that have a major impact of refractoriness. A case-control study is suitable for such an analysis, and to our knowledge has not previously been performed to assess this issue. Fifty-two refractory patients were compared with 52 control patients who were transfused at the same time. Only one transfusion event was analysed per patient. Clinical and laboratory data were recorded at the time of selected transfusion, and their association with refractoriness was investigated by the contingency table method and the Cox stepwise logistic regression. There were 16 (31%) patients with HLA antibodies in the index group and only one in the control group. The corrected count increment in the group of patients refractory due to HLA antibodies was significantly lower than that in non-alloimmunized refractory patients [median (range): 48.5 (-3560, 4614) and 4058 (-4417, 6886), respectively; U = 493, P < 0.0001]. In the multivariate analysis, factors associated with refractoriness were the presence of HLA antibodies (odds ratio (OR) 50.7; 95% CI 5.5-463); fever (odds ratio 7.2; 95% CI 2.5-21) and BMT because of chronic myeloid leukaemia (odds ratio 7.3; 95% CI 1.8-30). The latter two were the only factors that remained independently associated with refractoriness after excluding alloimmunized patients and their controls. We conclude that HLA antibodies are strongly associated with platelet transfusion refractoriness, but account for less than a third of these patients. Fever and BMT because of chronic myeloid leukaemia were the only non-immune factors independently associated with refractoriness.