Background and objectives: Pre-operative kidney volume is an independent predictor of glomerular filtration rate in renal cell carcinoma patients. Compensatory renal growth (CRG) can ensue prior to nephrectomy in parallel to tumor growth and benign parenchyma loss. We aimed to test whether renal metabolite abundances significantly associate with CRG, suggesting a causative relationship. Design, setting, participants, and measurements: Tissue metabolomics data from 49 patients, with a median age of 60 years, were previously collected and the pre-operative fold-change of their contra to ipsi-lateral benign kidney volume served as a surrogate for their CRG. Contra-lateral kidney volume fold-change within a 3.3 +/- 2.1 years follow-up interval was used as a surrogate for long-term CRG. Using a multivariable statistical model, we identified metabolites whose abundances significantly associate with CRG. Results: Our analysis found 13 metabolites in the benign (e.g. L-urobilin, Variable Influence in Projection, VIP, score = 3.02, adjusted p = 0.017) and 163 metabolites in the malignant (e.g. 3-indoxyl-sulfate, VIP score = 1.3, adjusted p = 0.044) tissues that significantly associate with CRG. Benign/tumor fold change in metabolite abundances revealed three additional metabolites with that significantly positively associate with CRG (e.g. p-cresol sulfate, VIP score = 2.945, adjusted p = 0.033). At the pathway level, we show that fatty-acid oxidation is highly enriched with metabolites whose benign tissue abundances strongly positively associate with CRG, both pre-opera-tively and long term, whereas in the tumor tissue significant enrichment of dipeptides and benzoate (positive association), glycolysis/gluconeogenesis, lysolipid and nucleotide sugar pentose (negative associations) sub-pathways, were observed. Conclusion: These data suggest that specific biological processes in the benign as well as in the tumor parenchyma strongly influence compensatory renal growth.