Presystemic degradation in the gastrointestinal tract is one of the major problems contributing to the poor oral absorption of antisense oligonucleotides. Complexes between the antisense phosphorothioate oligodeoxynucleotide ISIS 2302 and the polycationic carriers protamine sulfate grade X, protamine chloride grade V, protamine phosphate grade X, poly-L-lysine hydrobromide (PLL), spermidine phosphate salt, spermine diphosphate salt, and Protasan G113 and CL113 were formulated in order to increase stability against intestinal nucleolytic degradation. Specific conductivity measurements were carried out to determine the charge ratio of the complex systems. Nuclease stability assays were performed in a rat small intestine homogenate model, which displayed significant exo- and endonuclease activity. Full-length oligonucleotide and metabolites were analyzed by capillary gel electrophoresis with UV detection at 260 nm. Most of the complexes of ISIS 2302 and the polycationic materials, except PLL-based systems, showed a better protection against enzymatic metabolism than free oligonucleotide. Protamine sulfate and protamine chloride considerably enhanced the nuclease stability of the phosphorothioate antisense oligonucleotide. The association of oligonucleotides with several polycationic substances proved to be an alternative to chemical modification in order to stabilize oligonucleotides in the gastrointestinal tract against nucleolytic degradation.