Transplant rejection occurs when transplanted tissue is rejected by the recipient's immune system, which destroys the transplanted tissue. Transplant rejection can be lessened by determining the molecular similitude between donor and recipient and by use of immunosuppressant drugs after transplant.

Transplant rejection can be classified into three types: hyperacute, acute, and chronic. These types are differentiated by how quickly the recipient's immune system is activated and the specific aspect or aspects of immunity involved.

Hyperacute rejection is a form of rejection that manifests itself in the minutes to hours following transplantation. It is caused by the presence of pre-existing antibodies in the recipient that recognize antigens in the donor organ. These antigens are located on the endothelial lining of blood vessels within the transplanted organ and, once antibodies bind, will lead to the rapid activation of the complement system. Irreversible damage via thrombosis and subsequent graft necrosis is to be expected. Tissue left implanted will fail to work and could lead to high fever and malaise as the immune system acts against foreign tissue.

Graft failure secondary to hyperacute rejection has significantly decreased in incidence as a result of improved pre-transplant screening for antibodies to donor tissues. While these preformed antibodies may result from prior transplants, prior blood transfusions, or pregnancy, hyperacute rejection is most commonly from antibodies to ABO blood group antigens. Consequently, transplants between individuals with differing ABO blood types is generally avoided though may be pursued in very young children (generally under 12 months, but often as old as 24 months) who do not have fully developed immune systems. Shortages of organs and the morbidity and mortality associated with being on transplant waitlists has also increased interest in ABO-incompatible transplantation in older children and adults.

Acute rejection is a category of rejection that occurs on the timescale of weeks to months, with most episodes occurring within the first 3 months to 1 year after transplantation. Unlike hyperacute rejection, acute rejection is thought to arise from two distinct immunological mechanisms as lymphocytes, a subset of white blood cells, begin to recognize antigens on transplanted organ/graft. This recognition occurs due to the major histocompatibility complex (MHC), which are proteins on cell surface that are presented to the T-cell receptor found on T-cells. In humans, this is known as the human leukocyte antigen (HLA) system and over 17,000 HLA alleles or genetic variants have been described such that it is extremely uncommon for any two people to have identical alleles. Other non-HLA proteins, known as minor histocompatibility antigens, do exist but generally are unable to cause acute rejection in and of themselves unless a multitude of non-HLA proteins are mismatched. As such, HLA matching (in addition to matching ABO groups) is critical in preventing acute rejection.

This process of recognition by T-cells can happen directly or indirectly and lead to acute cellular and acute humoral rejection respectively. Direct allorecognition is a phenomenon within transplant immunology where the dendritic cells, which are the body's antigen-presenting cells (APCs), migrate from donor tissue to lymphoid tissue (lymphoid follicles and lymph nodes) in the recipient and present their MHC peptides to recipient lymphocytes. In comparison, indirect allorecognition is more analogous to how foreign antigens are recognized by the immune system. Dendritic cells of the recipient come across peptides from donor tissue whether in circulation, lymphoid tissue, or in donor tissue itself. Since not the result of direct antigen presentation, these may not necessarily be intact MHC molecules but instead other proteins that are deemed different enough from recipient may engender a response. This process leads to the priming of T-cells to respond to the peptides secondarily going forward. A third semi-direct pathway has been described in which recipient APCs present fully intact donor MHCs, yet its relative contribution to acute rejection is not as well understood.

Acute cellular rejection occurs following direct allorecognition of mismatched donor MHC by cytotoxic T-cells that begin to secrete cytokines to recruit more lymphocytes as well as cause apoptosis or cell death directly. The greater the difference in MHC between donor and recipient, the more cytotoxic T-cells are recruited to damage the graft, which may be seen via biopsy in solid organ transplants, with increased lymphocyte infiltration indicative of more severe acute cellular rejection. Acute humoral rejection is a process usually initiated by indirect allorecognition arising from recipient helper T-cells. These helper T-cells have a crucial role in the development of B-cells that can create donor-specific antibodies. The antibodies deposit themselves within the donor graft and lead to activation of the complement cascade alongside antibody-mediated cytotoxicity with neutrophils, a type of white blood cell separate from lymphocytes, predominantly infiltrating into tissues.

Barring genetically identical twins, acute rejection is to be expected to some degree. Rates of clinically significant acute rejection that could endanger transplant have decreased significantly with the development of immunosuppressive regimens. Using kidney transplants as an example, rates of acute rejection have declined from >50% in the 1970s to 10-20%. Singular episodes of acute rejection, when promptly treated, should not compromise transplant; however, repeated episodes may lead to chronic rejection.