Abstract: Sulindac sulfone (FGN-1, Aptosyn), a metabolite of the nonsteroidal anti-inflammatory drug sulindac, lacks cyclooxygenase inhibitory activity. Although its ability to inhibit tumorigenesis in both carcinogen-treated animals and patients with familial adenomatous polyposis has been attributed to the induction of apoptosis, its complete mechanism of action remains unclear. The purpose of the present study was to determine the ability of sulindac metabolites to regulate cellular levels of β-catenin and downstream targets of the adenomatous polyposis coli (APC)/β-catenin pathway in vitro. Sulindac sulfone was consistently more potent than the sulfide metabolite in all analyses, significantly decreasing the expression of total cellular β-catenin (50% of control), pro-caspase 3 (49%), cyclin D1 (51%), and PPARδ (65%) in SW480 cells. No significant alteration in pro-caspase 3 or β-catenin expression was found in HCA7, LS174, or Caco-2 cells treated with sulindac sulfone. A dose-dependent reduction in TCF-mediated transcriptional activity was also observed in SW480 cells. These data demonstrate that sulindac sulfone can modulate the APC/β-catenin pathway in vitro and that its efficacy is dependent upon the mutational status of APC and β-catenin.