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The overall objective of this study was to explore the possibility of utilizing polymeric delivery systems, Starburst PAMAM Dendrimers, with an Ethylene Diamine Core (EDA), as oligonucleotide carriers. The experiments compared the Caco-2 cell uptake of oligonucleotide-dendrimer complexes, formed in different ratios and with three different generations of dendrimers named D3, D5, and D7. PAMAM EDA dendrimers significantly enhanced (p ≤ 0.05, student t-test) the oligonucleotide uptake, in which D5 had the highest uptake. Agarose electrophoresis gel exhibited the complex formation, in which the charge and the size of the oligonucleotide-dendrimer complexes were varied with increasing dendrimer ratios and with different dendrimer generations. Oligonucleotides, 400 ng/ml, complexed to D3, D5, and D7 and formed in ratio from 1:1 up to 1:120, did not affect the Caco-2 cell membrane integrity up to 24-hours. The atomic force microscopy showed that while at ratio oligonucleotide-dendrimer D5 complexes showed a fluid-like morphology, however, at ratio 1:100 they displayed a spherical particle shape with a 20 run diameter. The oligonucleotide-dendrimer complex uptake had exhibited receptor-mediated endocytosis mechanism, in which the receptors were expressed mostly in the apical layer of Caco-2 cells. Dendrimers could be utilized as oligonucleotide carriers for oligonucleotide or gene therapy.