The purpose of this study is to investigate the feasibility of poly(arginine)8 (R8) modified poly(lactic-co-glycolic acid) (PLGA) nanoparticles as a carrier for the oral delivery of insulin. Insulin-loaded PLGA nanoparticle (INS-NP) was prepared by a double emulsion-solvent evaporation method, and R8 was subsequently conjugated to the surface of the INS-NP via polyethylene glycol bridge (R8-INS-NP). The physical and chemical features of the nanoparticles were characterized, and insulin release was determined in vitro. The pharmacokinetics and pharmacodynamics were evaluated by in situ absorption study with the intestinal loop of rats. The blood glucose level was determined by glucose oxidize method and the serum insulin concentration was determined by radioimmunoassay (RIA). The mean diameter of INS-NP was (179.0 +/- 5.2) nm and the polydispersity index was 0.152 +/- 0.042, while the entrapment efficiency was (29.10 +/- 2.59) %. The in vitro release behavior of insulin showed an initial burst effect followed by a stage of slow release. After administrating 10 U x kg(-1) insulin to rats, R8-INS-NPs decreased the plasma glucose level much lower than INS-NPs, meanwhile, D-form R8 substantially enhanced intestinal absorption of insulin much more than L-form R8. Compared to subcutaneous injection, the relative bioavailabilities of insulin were 0.52%, 4.78%, 8.39%, and the pharmacological bioavailabilities were 2.07%, 3.90%, 8.24%, separately. The R8-modified nanoparticles promoted the intestinal absorption of insulin, which might be a potential approach for oral delivery of peptide, protein and even other hydrophilic macromolecules in the future.