Objective To study the effect of anti-CD40L monoclonal antibody on the rejection of rat pancreatic islet xenografts and its mechanism. Methods The animal models of human-rat pancreatic islet xenografts were established and were treated with anti-CD40L monoclonal antibody. The levels of blood glucose of transplantation rats were measured and the survival of grafts and transplantation rats were observed after transplantation. The morphological changes of grafts were observed and the levels of cytokines (IL-2 and TNF-α) were quantified by ELISA. Results ①Level of blood glucose in all the rats with diabetes decreased to normal on day (2.3±0.2) after transplantation. The average level blood glucose of control group began to increase on day (8.1±0.6), while the treatment group began to increase on day (18.5±1.2) after transplantation, which was significantly postponed compared with control respectively (P＜0.01). ②Grafts of treatment group and control group survived for (22±8.2) and (10±2.1) days respectively. Survival of grafts in treatment group was significant longer than that in control group (P＜0.01). ③Survival of transplantation rats were (35±6.5) and (21±5.7) days in treatment group and control group respectively. The survival of transplantation rats in treatment group was significant longer than that in control group (P＜0.05). ④Levels of serum IL-2 and TNF-α in control group increased dramatically within (3.2±0.3) days and reached peak within (7.3±0.5) days after transplantation, which were significantly higher than those measured before transplantation (P＜0.01); While in treatment group, the levels of serum IL-2 and TNF-α began to increase on day (22.6±1.7) after transplantation, and reached peak on day (28.5±2.2), which was significantly postponed than those in control group (P＜0.01). Conclusion Anti-CD40L monoclonal antibody can inhibit the rejection of rat pancreatic islet xenografts and prolong the survival time of transplantation rats and grafts.