Genetic variants may increase susceptibility to both diabetes and kidney disease. Whether known diabetes-associated variants in the transcription factor 7-like 2 (TCF7L2) gene are associated with chronic kidney disease (CKD) progression and markers of kidney function is unknown. Participants of the Atherosclerosis Risk in Communities Study (ARIC; n = 11,061 self-identified white and n = 4014 black), Framingham Heart Offspring Cohort (FHS; n = 2468), and Heredity and Phenotype Intervention Heart Study (HAPI; n = 861) were genotyped at five (ARIC) and two (FHS) common TCF7L2 variants. The diabetes-conferring risk alleles at rs7903146 and rs7901695 were significantly associated with CKD progression among ARIC participants overall and among those without baseline diabetes. The overall adjusted hazard ratios per rs7903146 T allele were 1.17 (95% confidence interval [CI] 1.04 to 1.32) for white individuals and 1.20 (95% CI 1.03 to 1.41) for black individuals. Similarly, the overall hazard ratios per rs7901695 C allele were 1.19 (95% CI 1.06 to 1.34) for white individuals and 1.27 (95% CI 1.09 to 1.48) for black individuals. The FHS cohort supported these results: The rs7903146 T allele was significantly associated with lower estimated GFR (P = 0.01) and higher cystatin C (P = 0.004) in adjusted analyses overall and among those without diabetes. In the HAPI cohort, the rs7901695 C allele was significantly associated with lower estimated GFR in adjusted analyses (P = 0.049), as were several variants upstream and downstream of TCF7L2 (P < 0.003). No identified variant in the ARIC or FHS cohorts was associated with albuminuria. In conclusion, several population-based samples suggest that variants in the TCF7L2 gene are associated with reduced kidney function or CKD progression, overall and specifically among participants without diabetes.