Recurrent autoimmunity destroys nonobese diabetic (NOD) islet isografts, but whether recurrent autoimmunity contributes to islet graft destruction in immunocompetent allogeneic recipients is unknown. In the NOD, a single dose of streptozocin prevents or delays primary autoimmunity, allowing the detection of alloimmunity alone in chemically diabetic hosts (streptozocin-NOD) to be compared to the combined effects of autoimmunity and alloimmunity in spontaneously diabetic NODs (autoimmune-NOD). Islets were isolated from prediabetic NOD (H-2KdDb), nonobese resistant (NOR) (H-2KdDb), Balb/cByJ (H-2d) and B10.BR (H-2k) donors and transplanted to either the renal subcapsule or the intraportal site in autoimmune-NODs or streptozocin-NODs. MHC-matched NOR islets had in definite graft survival in streptozocin-NODs. However, NOR islets showed graft loss at 12.6 +/- 3.2 days in renal subcapsule and at 6.8 +/- 0.1 days in intraportal site of autoimmune-NODs. Partially MHC-matched Balb/cByJ islet grafts failed significantly sooner in autoimmune-NODs than in streptozocin-NODs (p < 0.005). Fully MHC-mismatched B10.BR islet grafts also failed sooner in autoimmune-NODs, but the difference did not reach significance (p < 0.06). Although the streptozocin-NOD was functionally tolerant of MHC-matched NOR islets, NOR islets transplanted into autoimmune-NODs failed sooner than NOD islets in both renal subcapsule (12.6 +/- 3.2 days vs. 26.4 +/- 10.5 days, p = 0.009) and intraportal sites (6.8 +/- 0.1 days vs. 11.5 +/- 1.7 days, p = 0.014). In the autoimmune-NODs, the intraportal site consistently showed shorter graft survival than the renal subcapsule site (NOD: p = 0.009, NOR: p = 0.014, Balb/cByJ: p = 0.008, B10.BR: p = 0.032). In conclusion, autoimmune processes facilitate the alloimmune response to minor and major histocompatibility antigens and accelerate graft destruction. The same autoimmune processes are more pronounced in the intraportal site.