Intercellular transfer of surface molecules has been demonstrated in vitro, or in vivo under artificial situations. Transplantation is a unique clinical situation in which foreign major histocompatibility complex (MHC) molecules are deliberately introduced. This provides a model to study intercellular MHC transfer because donor MHC molecules can easily be tracked. Here we describe the bidirectional transfer of MHC class II molecules between donor and recipient cells after transplantation of vascularized kidney and cardiac allografts in mice. Cells that are positive for both donor and recipient MHC class II accounted for up to 30% of the donor MHC class II⁺ population, suggesting that they play a significant role in the antigen presentation process. The majority of these cells were dendritic cells, but macrophages and B cells were also able to acquire foreign MHC molecules. Most doublepositive cells were also positive for costimulatory molecules, indicating a capability to elicit a T‐cell response. This transfer of MHC molecules between donor and recipient cells provides a link between the direct and indirect pathways of alloantigen presentation and suggests that MHC transfer is also likely to occur under normal physiological conditions, which has implications in the fields of infection, vaccination, and tumor immunology.— Brown, K., Sacks, S. H., Wong, W. Extensive and bidirectional transfer of major histocompatibility complex class II molecules between donor and recipient cells in vivo following solid organ transplantation. FASEB J. 22, 3776–3784 (2008)