Background and ObjectivesTransfusion support for immune‐mediated platelet refractoriness (PR) is clinically challenging, technically laborious and costly. The development of ‘EpHLA/EpVix software’ has been used successfully to select kidney donors. Here, we sought to evaluate this new software as a tool for platelet virtual crossmatch (VxM).Materials and MethodsThis is a prospective study from 2007 to 2014 of PR patients in a tertiary hospital. Platelet components selected by HLAMatchmaker program were crossmatched by EpHLA/EpVix, anti‐human globulin complement‐dependent lymphocytotoxicity test (AHG‐CDC), flow cytometry platelet crossmatch (FCxM) and then compared. Effectiveness of platelet components transfused was evaluated by CCI.ResultsNinety‐seven crossmatched platelet transfusions for 27 patients were enrolled. Partial matches were analysed for 75 transfusions by the 3 methods, and 22% showed discrepant results among the assays. After further analysis, data showed that all divergent cases could be explained by HPA alloimmunization, prozone effect (FCxM), low sensitivity of AHG‐CDC and possible interference in FCxM/AHG‐CDC assays. Notably, sensitivity and specificity of VxM analysis was excellent (100%). Satisfactory CCI counts were obtained for the majority (22/30) of the transfusions.ConclusionThe new EpHLA/EpVix method showed to be effective, feasible and fast for VxM at no cost and able to minimize labour on donor identification. However, platelet crossmatching may be a necessary step because EpHLA/EpVix does not formally exclude HPA alloimmunization.