Peroxisome proliferator-activated receptor gamma (PPARG) inactivation has been identified as an important step in colorectal cancer (CRC) progression, although the events involved have been partially clarified. UHRF1 is emerging as a cofactor that coordinates the epigenetic silencing of tumor suppressor genes, but its role in CRC remains elusive. Here, we report that UHRF1 negatively regulatesPPARGand is associated with a higher proliferative, clonogenic and migration potential. Consistently, UHRF1 ectopic expression inducesPPARGrepression through its recruitment on thePPARGpromoter fostering DNA methylation and histone repressive modifications. In agreement, UHRF1 knockdown elicits PPARG re-activation, accompanied by positive histone marks and DNA demethylation, corroborating its role inPPARGsilencing. UHRF1 overexpression, as well asPPARG-silencing, imparts higher growth rate and phenotypic features resembling those occurring in the epithelial-mesenchymal transition. In our series of 110 sporadic CRCs, high UHRF1-expressing tumors are characterized by an undifferentiated phenotype, higher proliferation rate and poor clinical outcome only in advanced stages III-IV. In addition, the inverse relationship withPPARGfoundin vitrois detectedin vivoand UHRF1 prognostic significance appears closely related toPPARGlow expression, as remarkably validated in an independent dataset. The results demonstrate that UHRF1 regulatesPPARGsilencing and both genes appear to be part of a complex regulatory network. These findings suggest that the relationship between UHRF1 andPPARGmay have a relevant role in CRC progression.