Transfusion-related acute lung injury (TRALI) is a serious adverse consequence of blood product transfusion. Cases of TRALI have gone unrecognized or misdiagnosed, since the symptoms can be confused with other transfusion-related events or with non-transfusion related comorbidities. Suspected cases of TRALI may be insufficiently investigated, and mild or moderate cases may not be investigated or reported at all. We report here the case of a 73-year man who developed TRALI following a transfusion of packed red blood cells (pRBCs) mediated by HLA class II antibodies (HLA-DR) detected by luminex technology. A very few cases of TRALI have been described being caused by HLA class II antibodies without the simultaneous presence of anti-HLA class I antibodies. Technology for antibody detection has increased the power and the specificity, especially with the use of flow cytometry with a better definition of the antigen/antibody pairs that have resulted in TRALI episodes. In this sense, HLA class II antibodies can exactly be detected with these methods and have surely been underestimated until now.