Glial‐cell‐line‐derived neurotrophic factor (GDNF) stimulates the survival of dopaminergic neurons. Little is known, however, about the possible immune sequelae of GDNF exposure or of exposure to other putative trophic factors. To address these questions, pieces of mesencephalic tissue, substantia nigra, from 15‐day‐old donor embryos were transplanted into the anterior chamber of the eye of adult male Sprague‐ Dawley recipient rats. At 5‐day intervals, an aliquot (0.5 µg) of GDNF, brain‐derived neurotrophic factor (BDNF), neurotrophin‐3 (NT‐3), or cytochrome‐C (CC) was injected into the anterior chamber of the eye of the recipients, and the sizes of the transplants were measured. GDNF increased transplant survival and growth. On day 42, all rats were sacrificed, and the grafts were evaluated by cresyl‐violet staining and by immunohistochemistry using antibodies raised against neurofilament (NF), tyrosine hydroxylase, or glial fibrillary acidic protein (GFAP), as well as the following monoclonai antibodies: OX‐38 anti‐CD4, OX‐8 anti‐CD8, OX‐18 anti‐MHC class I, OX‐6 anti‐ MHC class II, OX‐42 anti‐CD11b, R‐73 anti‐a and anti‐ß T‐cell receptor, and EDI raised against monocytes/macrophages. BDNF‐treated grafts showed only weak immunoreactivity, and even weaker reactions were seen in grafts treated with NT‐3, GDNF, or CC. No single immune system marker was significantly elevated in grafts from any treatment group. We used OX‐42 and EDI to study possible alterations of microglial components. Ramified microglial cells were found in GDNF‐treated grafts and to a lesser extent in NT‐3 and BDNF‐treated grafts. EDl‐labeled reactive microglial components were found in NT‐3‐ and BDNF‐treated grafts. Additionally, large and rounded OX‐42‐positive phagocytic cells were found in NT‐3‐treated grafts. Together with our previous finding that GDNF treatment of spinal cord transplants activates immune responses and leads to microglial activation, our data dempnstrate that although treatment with GDNF and to some degree with BDNF can enhance immune responses to immunogenic grafts, such as fetal spinal cord grafts, but the trophic factors per se do not elicit any marked response in non‐immunogenic grafts like substantia nigra.