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In lung transplantation, there is a increased recognition on the deleterious role of DSA for chronic dysfunction of pulmonary graft. In order to optimize the therapeutic stategies and to guide clinical trials, the standardized definition of humoral reject (HR) criteria in lung transplantation proves to be necessary. The deposit of C4d complement, confirming the activation of secondary complement in interaction between DSA and target cells, is a reliable biomarker of HR in renal and cardiac transplantations. However, with the same histopathological criteria from HR of kidney and heart, which is less robust when applying in lung transplantation. The sometime contradictory results of C4d are in part linked to variability between medical centers and in the interpretation of this marker. Although no definition of the criteria of HR had been established, ISHLT (International Society for Heart and Lung Transplantation) recommends a multidisciplinary approach to HR for lung transplantation, including the tripod diagnosis: 1) presence of clinical dysfunction, 2) presence of DSA and 3 ) presence of histopathological lesions of C4d with endothelial deposit in the alveolar capillaries.