Colorectal cancer (CRC) is one of the leading causes of deaths in the United States. Roughly 150,000 new cases are diagnosed each year, resulting in ~50,000 deaths. About 10-30% of CRC patients harbor either loss of or missense mutations in SMAD4, a critical component of the TGF-β signaling pathway. Our lab and others have shown that complete loss of Smad4 results in the increase in tumor size, microvascular density, and frequency of metastasis in CRC xenograft models. While the role of Smad4 loss in CRC progression has been extensively studied, the pathophysiological function of missense mutations in Smad4 is not fully understood. At the molecular level, these mutations usually map to the MH2 domain and eliminate residues that are involved in the formation of the heteromeric complex with regulatory Smads (R-Smads) such as Smad2/3 and ensuing transcriptional activation. These detrimental effects suggest that SMAD4 missense mutations can be categorized as loss-of-function (LOF). However, uncharacteristically for LOF mutations, they cluster in a few hotspots (e.g., R361), which is more consistent with a gain-of- or neomorphic function. Here, we investigated the functional role of Smad4 R361 mutants in vitro by re-expressing two R361 Smad4 variants in Smad4-null CRC cells. As predicted, R361 mutations disrupted Smad2/3-Smad4 heteromeric complex formation and abolished canonical TGF-β downstream signaling. In that, they were similar to SMAD4 loss. However, RNA sequencing and subsequent RT-PCR revealed that Smad4mut cells possess the known gene signature associated with enhanced LEF1 protein function and increased WNT signaling. Mechanistically, Smad4 mutant proteins retained binding to LEF1 protein and directed a commensurate increase in downstream Wnt signaling as measured by TOP/FOP luciferase assay. Consistent with these findings, human CRCs with SMAD4 missense mutations were less likely to acquire activating mutations in the key Wnt pathway gene CTNNB1 (encoding beta catenin) than CRCs with truncating SMAD4 nonsense mutations. The former was also associated with shorter survival. Collectively, these studies implicate a TGF-β ligand-independent gain of function role for mutant Smad4 in CRC.