As adenoviral vectors are extensively used for genetic manipulation of insulin producing cells in vitro there is an increasing need to evaluate their effects on the function, morphology and viability of transduced pancreatic islets. In the present study, we observed that specific adenoviral genotypes, carrying E4- and E1/E3-deletions correlate with differential induction of necrosis in pancreatic islet cells. In particular, the adenovirus death protein encoded from the E3-region of the adenoviral genome was able to modulate the changes induced in the morphology and viability of the transduced cells. We also propose a putative role for the transcriptional regulator pIX. Although human islet cells showed an increased resistance in terms of viral concentrations required for the induction of cell-toxicity, our results showed that they were unable to build up an efficient antiviral response following transduction and that their survival was dependent on the exogenous addition of -interferon. An intact and fully functional -cell is crucial for the successful application of gene therapy approaches in type 1 diabetes and therefore, the implications of our findings need to be considered when designing vectors for gene transfer into pancreatic -cells.