BACKGROUND: Type l diabetes mellitus is a T cell-mediated autoimmune disease resulting in pancreatic islet cell damage. In this study, immunotherapy was used to deal with type l diabetes mellitus and stem cell transplantation was used to repair damaged islet p cells, attempting to explore a new treatment for type l diabetes mellitus. OBJECTIVE: To observe the efficacy of human umbilical cord mesenchymal stem cells combined with immunotherapy for the treatment of type l diabetic mice. METHODS: Fifty BALB/c Foxp3-DTR-EGFP positive mice were selected, six of which were randomly selected as normal control group and the remaining of which were intraperitoneally injected with streptozotocin and diphtheria toxin to prepare an animal model of type l diabetes mellitus. After successful modeling, randomization was performed in model mice and there were four groups: model group (normal saline), immunotherapy group (subcutaneous injection of dexamethasone (10 μg) and insulin (10 μg) mixture), cell transplantation group (injection of human umbilical cord mesenchymal stem cells (1 X106 cells per mouse) through the tail vein, and combined treatment group (the combination of immunotherapy and cell transplantation as described above). At 4 weeks after treatment, changes in blood glucose, C-peptide, body mass, pancreatic histopathology and insulin-positive area were observed in each group. RESULTS AND CONCLUSION: (1) Compared with the normal control group, the blood glucose level of the model group increased (P < 0.01) the C peptide level and body mass decreased (P < 0.01), and the islet was severely atrophied, with decreased number of islet cells and reduced insulin-positive area. (2) Compared with the model group, the blood glucose level of the immunotherapy group decreased (P > 0.05), the C-peptide level and body mass did not change significantly (P > 0.05), the islet cells increased in number, and the insulin-positive area increased. (3) Compared with the model group, the blood glucose level of the cell transplantation group and the combined treatment group decreased (P > 0.05), the C peptide level and body mass increased (P < 0.05), the islet cells increased in number, and the insulin-positive area increased. These findings reveal that either human umbilical cord mesenchymal stem cells or immunotherapy can improve the islet function of type l diabetic mice, and the combination treatment has better outcomes.