Background The International Society for Heart and Lung Transplantation (ISHLT) recently established a diagnostic scheme for antibody-mediated rejection (AMR). Currently, however, confirmatory immunohistochemistry studies are recommended only if AMR is clinically or histologically suspected. In this study, we examine whether a pattern of repetitive AMR occurred early enough after transplantation to warrant prospective immunohistochemistry screening in all recently transplanted recipients. Methods We queried our pathology database of adult and pediatric endomyocardial biopsies (EMBs) from 1985 to 2005. All EMB specimens were prospectively studied by immunofluorescence in the early post-operative period. AMR was defined as the presence of complement and immunoglobulin deposits on frozen section. Only patients classified as antibody-mediated rejectors (≥3 episodes of AMR) were included. Cumulative incidence and time from transplant to first and third AMR episodes were obtained. Results Three hundred seventy-five of 870 heart transplant recipients had ≥3 episodes of AMR. Mean age of recipients was 45.6 years and 78% were male. A total of 19,569 EMBs comprised the study data. By 100 days post-transplant, 85% of patients had their first and 54% their third AMR. In addition, patients showed a clear trend of early clustering of AMR-positive biopsies. Results were similar regardless of whether or not muromonab-CD3 (Orthoclone OKT3) induction was used. Conclusions We advocate early immunohistochemical surveillance testing for AMR to supplement the diagnostic algorithm established by the ISHLT, because a pattern of AMR becomes manifest soon after transplantation. This change will allow earlier detection of asymptomatic AMR and may prompt changes in immunosuppression strategies to avoid adverse outcomes.