To study the effect of expression of a single foreign antigen on the outcome of otherwise compatible mouse islet grafts, we have used transgenic mice expressing the human complement receptor 2 (CR2, CD21, C3d/EBV receptor) on their pancreatic (β-cells (RIPCR2 mice). Donors were RIP-CR2 mice, typed at the major histocompatibility complex (MHC) as H-2^k, H-2^b, or H-2^bxk, and recipients were streptozotocintreated nontransgenic B6 × CBA Fl mice (H-2^bxk). H-2^b or H-2^bxk CR2-expressing islets were not rejected (mean survival time [MST] >100 days) but induced a peri-insulitis and an antibody response to CR2. In contrast, H-2^k CR2-expressing islets were rejected in 80% of the cases with a MST of 65 ± 23 days and were massively infiltrated by a destructive insulitis. In both cases, the infiltrate was mainly made of CD4⁺ cells, with few CD8⁺ cells. The isotype of IgG antibody response to CR2 was studied: recipients of H-2^k grafts had a predominantly IgGl response, while recipients of H-2^b grafts had a balanced IgG2a and IgGl response. To further evaluate the mechanism of differential rejection of the two types of grafts, recipients were immunized with CR2-expressing rat insulinoma cells before transplantation. Preimmunization with CR2 did not affect the outcome of H-2^b grafts but greatly accelerated the rejection of H-2^k grafts. These experiments indicate that expression of a single foreign antigen on β-cells triggers an immune response leading to rejection or to peri-insulitis, depending on the MHC of donor islets.