Variants of the transcription factor 7-like 2 gene (TCF7L2) have been associated with type 2 diabetes and cardiovascular disease in different populations. Here we investigated the potential association of the rs7903146 polymorphism in the TCF7L2 gene with clinical profile of end-stage renal disease (ESRD) patients. We examined a cohort of 1065 ESRD patients with diabetic and non-diabetic renal disease. The control group consisted of 924 healthy individuals. All subjects were genotyped for the rs7903146 single nucleotide polymorphism by polymerase chain reaction. The genotype distribution and allele frequencies were significantly different between ESRD patients and controls (p < 0.01). The OR for the TT genotype was 2.81 (95% CI 2.08-3.79). Genotype and allele frequencies were compared between subgroups of patients with different clinical phenotypes. The frequency of the T allele was significantly higher in patients with diabetic nephropathy versus non-diabetic renal disease (p = 0.007, OR 1.70, 95% CI 1.36-2.11). The statistically significant differences were demonstrated between patients with and without cardiovascular disease, with the OR for T allele 1.57 (95% CI 1.31-1.90). The odds ratio for TT genotype was 2.38 (95% CI 1.62-3.51). In our study the T allele of the rs7903146 SNP in the TCF7L2 gene confers the risk of developing diabetic nephropathy. We described for the first time a strong relationship between the TCF7L2 gene variant rs7903146 and cardiovascular disease in end-stage renal disease patients.