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Activation of pancreatic β-cell proliferation has been proposed as an approach to replace reduced functional β-cell mass in diabetes. Quiescent fibroblasts exit from G0 (quiescence) to G1 through pRb phosphorylation mediated by cyclin C/cdk3 complexes. Overexpression of cyclin D1, D2, D3, or cyclin E induces pancreatic β-cell proliferation. We hypothesized that cyclin C overexpression would induce β-cell proliferation through G0 exit, thus being a potential therapeutic target to recover functional β-cell mass. We used isolated rat and human islets transduced with adenovirus expressing cyclin C. We measured multiple markers of proliferation: [3H]thymidine incorporation, BrdU incorporation and staining, and Ki67 staining. Furthermore, we detected β-cell death by TUNEL, β-cell differentiation by RT-PCR, and β-cell function by glucose-stimulated insulin secretion. Interestingly, we have found that cyclin C increases rat and human β-cell proliferation. This augmented proliferation did not induce β-cell death, dedifferentiation, or dysfunction in rat or human islets. Our results indicate that cyclin C is a potential target for inducing β-cell regeneration., This work was supported by grants from ISCIII-Subdirección General de Evaluación y Fomento de la Investigación, Spain (PS09/00671); Programa Ramón y Cajal (RYC-2011-08101) Ministerio de Economía y Competitividad, Spain; and Europe-FP7 Marie Curie grant (IRG-247835) to I. Cózar-Castellano, by Europe-FP7 Marie Curie grant (IRG-256369) to G. Perdomo, by National Institute of Diabetes and Digestive and Kidney Diseases Grants (RO1-DK-073716;, DK-084236) and Juvenile Diabetes Research Foundation (17-2013-416) to E. Bernal-Mizrachi, and by a Minority Postdoctoral Fellowship from the American Diabetes Association to M. Jiménez-Palomares.