The poor outcome of intraportal islet transplantation may be explained by the instant blood-mediated inflammatory reaction (IBMIR), characterized by islet entrapment in blood clots, leucocyte infiltration and disruption of islet morphology. Here we employ a newly developed in vitro system to identify the blood cells involved in this process. Islets were mixed with ABO-compatible blood in heparinized tubes and incubated for various times up to 6 h. Clots were analysed immunohistochemically for detection of platelets (CD41a), leucocytes/lymphocytes (CD11b), granulocytes (CD16, lysozyme), neutrophilic granulocytes (neutrophil elastase), eosinophilic granulocytes (NaCN + H₂O₂), macrophages (CD68), dendritic cells (CD209/DC-SIGN), B cells (CD20) and T cells (CD4, CD8). Platelets were rapidly deposited around the islets in contact with the blood, reaching a maximum by 30 min. The first neutrophilic granulocytes appeared in the islets after 15 min, increased at 1 h and peaked at 2 h. Small numbers of macrophages were found infiltrating the islets already after 5 min, with a slight increase over time. However, control stainings of cultured islets and pancreas biopsies identified these cells as being largely of donor origin. No T cells, B cells, dendritic cells or eosinophilic granulocytes were detected during the 6 h observation time. Neutrophilic granulocytes were identified as the main infiltrating blood cell in islets exposed to blood, implying that these cells play a key role in clinical islet transplantation. Because islets are known to be exquisitely susceptible to oxidative stress, development of drugs targeting neutrophilic cytotoxicity could markedly improve the outcome of islet transplantation.