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Precise diagnosis of antibody‐mediated rejection (AMR) in cardiac allograft endomyocardial biopsies (EMBs) remains challenging. This study assessed molecular diagnostics in human EMBswith AMR. A set of 34 endothelial, natural killer cell and inflammatory genes was quantified in 106 formalin‐fixed, paraffin‐embedded EMBsclassified according to 2013 International Society for Heart and Lung Transplantation (ISHLT) criteria. The gene set expression was compared between ISHLTdiagnoses and correlated with donor‐specific antibody (DSA), endothelial injury by electron microscopy (EM) and prognosis. Findings were validated in an independent set of 57 EMBs. In the training set (n = 106), AMRcases (n = 70) showed higher gene set expression than acute cellular rejection (ACR; n = 21, p < 0.001) and controls (n = 15, p < 0.0001). Anti‐HLA DSApositivity was associated with higher gene set expression (p = 0.01). Endothelial injury by electron microscopy strongly correlated with gene set expression, specifically in AMRcases (r = 0.62, p = 0.002). Receiver operating characteristic curve analysis for diagnosing AMRshowed greater accuracy with gene set expression (area under the curve [AUC] = 79.88) than with DSA(AUC= 70.47) and C4d (AUC= 70.71). In AMRpatients (n = 17) with sequential biopsies, increasing gene set expression was associated with inferior prognosis (p = 0.034). These findings were confirmed in the validation set. In conclusion, biopsy‐based molecular assessment of antibody‐mediated microcirculation injury has the potential to improve diagnosis of AMRin human cardiac transplants. This study assesses a set of 34 endothelial, natural killer cell and inflammatory genes for molecular diagnostics in human formalin‐fixed, paraffin‐embedded heart allograft biopsies, and suggests that biopsy‐based molecular assessment of antibody‐mediated microcirculation injury has the potential to improve diagnostics from cardiac transplants.