Hyperactivated α2-6-sialylation on N-glycans due to overexpression of the Golgi enzyme β-galactoside: α2-6-sialyltransferase (ST6Gal-I) often correlates with cancer progression, metastasis, and poor prognosis. This studywas aimed to determine the association between ST6Gal-I expression and the risk of recurrence and survival ofpatients with localized clear-cell renal cell carcinoma (ccRCC) following surgery. We retrospectively enrolled 391patients (265 in training cohort and 126 in validation cohort) with localized ccRCC underwent nephrectomy at asingle center. Tissue microarrays were constructed for immunostaining of ST6Gal-I. Prognostic value and clinicaloutcomes were evaluated. High ST6Gal-I expression was associated with Fuhrman grade (p<0.001 and p=0.016,respectively) and the University of California Los-Angeles Integrated Staging System (UISS) score (p=0.004 andp=0.017, respectively) in both cohorts. Patients with high ST6Gal-I expression had significantly worse overallsurvival (OS) (p<0.001 and p<0.001, respectively) and recurrence free survival (RFS) (p<0.001 and p=0.002,respectively) than those with low expression in both cohorts. On multivariate analysis, ST6Gal-I expressionremained associated with OS and RFS even after adjusting for the UISS score. Stratified analysis suggestedthat the association is more pronounced among patients with low and intermediate-risk disease defined by theUISS score. High ST6Gal-I expression is a potential independent adverse predictor of survival and recurrencein ccRCC patients, and the prognostic value is most prominent in those with low and intermediate-risk diseasedefined by the UISS score.