While it is well established that peroxisome proliferator activated receptor gamma (PPARgamma) ligands inhibit cell growth and induce apoptosis of colon cancer cells with a prolonged treatment (3-5 days), the early effects of PPARgamma exposure are less clear. In this report, we demonstrate that the PPARgamma ligand, ciglitazone, induces proliferation of HT-29 and Caco-2 colon cancer cells transiently (<48 h) prior to a decrease in cell proliferation (>72 h). Associated with this cellular proliferation phase, we observed an increase in NF-kappaB transcriptional activity. Ciglitazone exposure did not affect NF-kappaB DNA binding but rather, increased phosphorylation of p65 as well as the recruitment of the co-activator CBP. Pre-treatment of HT-29 cells with wortmannin, a phosphatidylinositol 3-kinase (PI3K) kinase inhibitor, inhibited ciglitazone-induced p65 phosphorylation, NF-kappaB transcriptional activity and cell proliferation. Interestingly, ciglitazone inhibited PPAR transcriptional activity, suggesting this early proliferative effect is PPRE independent. These data suggest that the early proliferative phase of PPARgamma ligand exposure is associated with activation of NF-kappaB by p65 phosphorylation and cofactor recruitment and not through increased DNA binding.