Background In this study we investigate whether pro-apoptotic, pro-inflammatory and other early signaling markers indicative of increased propensity for cell death processes were evident in human donor heart allografts immediately before transplantation, and whether there is an association with primary graft failure. Methods A prospective study was performed utilizing donor left atrial myocardium collected at the time of implantation of hearts from brain-dead donors (BDD, n = 29). In addition, to explore the potential of donor hearts from donation after circulatory death (DCD), myocardial samples were obtained during transplantation of lungs from DCD donors (n = 6). A comparator reference group (n = 7) consisted of left atrial specimens from patients undergoing mitral valve surgery. Results Significantly raised levels of caspase-3 specific activity, activated hypoxia inducible factor-1 (HIF-1a) and 8-hydroxy-2 -deoxyguanosine were evident in the transplanted hearts (from BDD) that developed primary graft failure (n = 11). DCD hearts did not differ from BDD with regard to mRNA expression levels of FAS, Bax, IL-6 and caspase-3. Although DCD hearts exhibited lower caspase-3 specific activity and activated hypoxia-inducible factor-1 protein, they had higher levels of mRNA for NF-?B, Bnip3 and caspase-1 mRNA. Increased 8-hydroxy-2 -deoxyguanosine levels reflected greater oxidative stress and reactive oxygen species-related DNA fragmentation. Conclusions Our data indicate a significant role of pro-apoptotic and pro-inflammatory activity in allografts that subsequently exhibit primary graft failure. The relatively lower levels of apoptotic and inflammatory activity in DCD hearts suggest they may represent a potentially usable donor cardiac allograft pool. This possibility requires further detailed molecular and clinical research.