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Introduction: In autosomal dominant polycystic kidney disease (ADPKD) patients, predicting renal disease progression is important to make a prognosis and to support the clinical decision whether to initiate renoprotective therapy. Conventional markers all have their limitations. Metabolic profiling is a promising strategy for risk stratification. We determined the prognostic performance to identify patients with a fast progressive disease course and evaluated time-dependent changes in urinary metabolites. Methods: Targeted, quantitative metabolomics analysis (H-1 NMR-spectroscopy) was performed on spot urinary samples at two time points, baseline (n = 324, 61% female; mean age 45 years, SD 11; median eGFR 61 mL/min/1.73 m(2), IQR 42-88; mean years of creatinine follow-up 3.7, SD 1.3) and a sample obtained after 3 years of follow-up (n = 112). Patients were stratified by their eGFR slope into fast and slow progressors based on an annualized change of > -3.0 or <= -3.0 mL/min/1.73 m(2)/year, respectively. Fifty-five urinary metabolites and ratios were quantified, and the significant ones were selected. Logistic regression was used to determine prognostic performance in identifying those with a fast progressive course using baseline urine samples. Repeated-measures ANOVA was used to analyze whether changes in urinary metabolites over a 3-year follow-up period differed between fast and slow progressors. Results: In a single urinary sample, the prognostic performance of urinary metabolites was comparable to that of a model including height-adjusted total kidney volume (htTKV, AUC = 0.67). Combined with htTKV, the predictive value of the metabolite model increased (AUC = 0.75). Longitudinal analyses showed an increase in the myoinositol/citrate ratio (p < 0.001) in fast progressors, while no significant change was found in those with slow progression, which is in-line with an overall increase in the myoinositol/citrate ratio as GFR declines. Conclusion: A metabolic profile, measured at a single time point, showed at least equivalent prognostic performance to an imaging-based risk marker in ADPKD. Changes in urinary metabolites over a 3-year follow-up period were associated with a fast progressive disease course.