Background <p>Urothelial Bladder Cancer (UBC) remains a significant clinical challenge due to its high morbidity, substantial economic burden, and high recurrence rates. E-cadherin, an important regulator of cell-cell adhesion encoded by the <i>CDH1</i> gene, is frequently downregulated during malignant progression, serving as a hallmark of invasiveness. This study explored the prognostic significance of <i>CDH1</i> genetic variants (rs16260 C &gt; A and rs7186053 A &gt; G) and haplotypes, while integrating bioinformatic profiling of repetitive elements.</p> Methods and results <p>A cohort of 334 UBC patients was genotyped via qPCR, followed by haplotype reconstruction and association with clinical outcomes. This analysis was complemented by immunofluorescence to illustrate the interplay between tissue invasion levels and <i>CDH1</i> genetic backgrounds in selected samples. Bioinformatic tools characterized the <i>CDH1</i> genomic repeat elements landscape. The rs16260 heterozygous genotype was significantly associated with a reduced risk of 1-year recurrence (<i>p</i> &lt; 0.05). Moreover, the CG haplotype emerged as a protective factor against recurrence within two years. Illustrative immunofluorescence analysis confirmed the loss of E-cadherin and epithelial disorganization in muscle-invasive samples compared to non-invasive tumors. Notably, bioinformatic screening revealed a complex architecture of repetitive elements, including novel <i>Alu</i> insertions within Exon 16, indicating potential regulatory hubs.</p> Conclusion <p>Our findings demonstrate that <i>CDH1</i> polymorphisms and haplotype structures are potential modulators of UBC recurrence. Furthermore, the identification of repetitive elements in crucial genomic segments highlights a new layer of transcriptional regulation, offering promising approaches for the prognostic stratification and molecular targeting of bladder cancer.</p> Graphical abstract <p></p>