The prostate apoptosis response protein 4 (Par-4), a tumor suppressor, has been shown to induce apoptosis in cancer cells. While reduced Par-4 expression has been linked to survival of some cancers, its involvement in colon cancer has not been well documented. To explore the feasibility of increasing Par-4 in colon cancer to induce apoptosis, the human colon cancer cell line, HT29, was transfected to overexpress Par-4. In these cells, overexpressed Par-4 led to increased apoptosis in the presence of 5-fluorouracil. Subsequently, PAR-4 cDNA was packaged in nanoliposomal particles. Treating cells with the Par-4 nanoliposomes also increased susceptibility to 5-FU. These nanoliposomes were used to deliver Par-4 plasmid to tumors growing in nude mice from wild type HT29 cells. Results showed that nanoliposomes effectively delivered plasmid DNA to tumors in vivo. Again, tumors in mice treated with the Par-4 nanoliposomes were more susceptible to 5-FU treatment. This suggests that upregulation of Par-4 expression is a potentially useful mechanism to enhance the current chemotherapeutic regimen for colon cancer. Packaging Par-4 cDNA in nanoliposomal particles is a promising delivery method to increase response to chemotherapy.