Attachment of donor cells to microcarriers has been reported to make them more tolerable for transplantation into the brain. Human retinal pigment epithelial (hRPE) cells have been previously reported to contain enzymes for the production of dopa. Therefore, we examined the host immune response and behavioral effects of xenotransplantation of hRPE cells attached to microcarriers (hRPE-M) into the striatum of unilateral dopamine-depleted rats. Thirty-four adult rats were lesioned with 6-OHDA injections into the medial forebrain bundle on the right side. After 5 weeks of testing for apomorphine-induced rotations (AIR), animals were randomized for right striatal surgery into the following four groups: hRPE-M (group 1), hRPE alone (group 2), microcarriers alone (group 3), or needle tract alone (group 4). Following surgery, animals were tested for AIR every 4 weeks for a period of 12-18 weeks and thereafter euthanized. There was a significant reduction in AIR scores posttransplantation in all groups of animals in the initial observation points at 4 weeks and 8 weeks. However, there was a gradual return to baseline scores in groups 2, 3, and 4 animals at 12 weeks and at 18 weeks only group 1 animals had statistically significant (p = 0.001, repeated measures ANOVA, means comparison, predetermined contrasts) reduction in AIR scores. Brain tissue from representative animals from each group was cut into 30-microm coronal sections, stained for cresyl violet, tyrosine hydroxylase (TH), and markers for host immune activation. Sections through the striatum from group 1 animals revealed microcarriers with attached cells resembling RPE cells. No evidence of transplanted hRPE cells could be detected in sections from group 2 animals while those from groups 3 and 4 animals showed microcarriers and a needle tract alone, respectively. There was no host TH-immunoreactive sprouting response in the striatum in any of the groups and the host immune response was minimal. These results suggest that intrastriatal hRPE-M xenotransplantation into rats is well tolerated without systemic immunosuppression and that such transplants may provide behavioral benefit for parkinsonism.