Exendin‐4 can stimulate β‐cell replication in mice. Whether it can stimulate β‐cell replication in human islet grafts remains unknown. Therefore, we compared the effects of exendin‐4 on β‐cell replication in mouse and human islet grafts. Islets, isolated from mouse and human donors at different ages, were transplanted into diabetic mice and/or diabetic nude mice that were given bromodeoxyuridine (BrdU) with or without exendin‐4. At 4 weeks post‐transplantation, islet grafts were removed for insulin and BrdU staining and quantification of insulin⁺/BrdU⁺ cells. Although diabetes was reversed in all mice transplanting syngeneic mouse islets from young or old donors, normoglycemia was achieved significantly faster in exendin‐4 treated mice. Mouse islet grafts in exendin‐4 treated mice had significantly more insulin⁺/BrdU⁺β cells than in untreated mice (P < 0.01). Human islet grafts from ≤22‐year‐old donors had more insulin⁺/BrdU⁺β cells in exendin‐4 treated mice than that in untreated mice (P < 0.01). However, human islet grafts from ≥35‐year‐old donors contained few insulin⁺/BrdU⁺β cells in exendin‐4 treated or untreated mice. Our data demonstrated that the capacity for β‐cell replication in mouse and human islet grafts is different with and without exendin‐4 treatment and indicated that GLP‐1 agonists can stimulate β‐cell replication in human islets from young donors.