Covalent attachment of polymers to cells and tissues could be used to solve a variety of problems associated with cellular therapies. Insulin-dependent diabetes mellitus is a disease resulting from the autoimmune destruction of the beta cells of the islets of Langerhans in the pancreas. Transplantation of islets into diabetic patients would be an attractive form of treatment, provided that the islets could be protected from the host's immune system in order to prevent graft rejection. If reaction of polyethylene glycol (PEG) segments with the islet surface did not damage function, the immunogenicity and cell binding characteristics of the islet could be altered. To determine if this process damages islets, rat islets have been isolated and treated with protein-reactive PEG-isocyanate (MW 5000) under mild reaction conditions. An assessment of cell viability using a colorimetric mitochondrial activity assay showed that treatment of the islets with PEG-isocyanate did not reduce cell viability. Insulin release in response to secretagogue challenge was used to evaluate islet function after treatment with the polymer. The insulin response of the PEG-treated islets was not significantly different than untreated islets in a static incubation secretagogue challenge. In addition, PEG-isocyanate-treated islets responded in the same manner as untreated islets in a glucose perifusion assay. Finally, the presence of PEG on the surface of the islets after treatment with the amine-reactive N-hydroxysuccinimide-PEG-biotin (not PEG-isocyanate) was confirmed by indirect fluorescence staining. These results demonstrate the feasibility of treating pancreatic islets with reactive polymeric segments and provide the foundation for further investigation of this novel means of potential immunoisolation.