The aim of this study was to investigate whether treatment with rapamycin plus vildagliptin restores beta-cell function in patients with long-standing type 1 diabetes.A phase 2, single-center randomized, double-blind, placebo-controlled study was conducted in long-standing type 1 diabetes patients randomized (1:1:1) to 4 weeks rapamycin (Group 2), 4 weeks rapamycin plus 12 weeks vildagliptin (Group 3) or double placebo (Group 1). Primary outcome was the proportion of participants with a positive response to the Mixed Meal Tolerance Test (C-peptide at 90 min >0.2 nmol/L) at week 4 and 12. Secondary endpoints included insulin requirement, standard measures of glycemic control, hormonal and immunological profile.Fifty-five patients were randomized to Group 1 (n=18), Group 2 (n=19) or Group 3 (n=18). No patient in any group showed a positive C-peptide response and there was no significant difference at 4 and 12 weeks for the primary outcome. At four week insulin requirement decreased from 0.54 to 0.48 U/kg/day in Group 2 (p = 0.013), from 0.59 to 0.51 U/kg/day in Group 3 (p <0.001), while it did not change in Group 1. At 12 week HbA1c significantly decreased both in Group 2 [from 7.3% (56 mmol/mol) to 7% (53 mmol/mol); p= 0.045] and in Group 3 [from 7.2% (55.5 mmol/mol) to 6.9% (52 mmol/mol); p=0.001]. Rapamycin treatment was associated with a decrease in insulin antibody titer and changes in hormonal/immunological profile.Rapamycin reduced insulin requirement, but did not restore beta-cell function in patients with long-standing type 1 diabetes.