Abstract： Objective To study the effect of CTLA4Ig and rapamycin therapy on islet xenotransplantation. Methods Streptozotocin-induced diabetic C57BL/6 mice were transplanted (Tx) under the kidney capsule with rat islets and randomly divided into following groups: group 1, control group, i.e. islet Tx without any therapy; group 2, rapamycin group (0. 2 mg/kg by oral garage at day 0, 1, 2 and every other day to 14); group 3, anti-CD154 mAb (MRI) group (0. 5 mg i. p on day 0, 2 and 4); group 4, CTLA4Ig group (0. 5 nag i. p on day 0, 2, 4 and 6); group 5 (combination therapy with CTLA4Ig and rapamycin); group 6 (combination therapy with CTLA4Ig and MR1);group 7 (combination therapy with CTLA4Ig, MR1 and rapamycin). Mice were followed for islet function by glycemia and histology was performed at time of rejection and 200 days after Tx. Results Rapamycin, MR1, CTLA4Ig therapy alone significantly prolonged rat xenograft survival compared to control group [median graft survival (MGS) 34 days, 98 days and 77 days vs. 17 days, respectively,P＜0. 05), but rejection still occurred. Combination therapy of CTLA4Ig + rapamycin allowed significantly prolonged graft survival compared with control group (MGS 130 days) (P＜0. 01 ). Combination therapy of CTLA4Ig + MR1 and CTLA4Ig + MR1 + rapamycin allowed indefinite graft survival (MGS ＞200 days and ＞200 days respectively). Histological analysis showed severe xenografts destruction at rejection. At day of 200 post-Tx, CTLA4Ig + rapamycin treated mouse grafts showed positive staining for insulin and glucagon, and no cellular infiltration within the grafts. Conclusion Long-term survival of concordant islet xenografts was achieved by combination therapy of CTLA4Ig and rapamycin.