Introduction: Tuberous Sclerosis Complex (TSC) is an autosomal dominant disease that affects nearly 2 million people worldwide. In most cases, mutations in either TSC2 (70%), or TSC1 (20%) induce the growth of benign tumors in multiple organ systems. Angiomyolipomas (AMLs) are benign tumors associated with TSC and are specific to the kidney. Importantly, approximately 40% of pediatric TSC patients will have cysts and/or AMLs by age 10. It is currently unclear why AMLs develop at different stages in life as the mechanisms of incomplete penetrance has yet to be elucidated. Importantly, metabolic changes occur in TSC cells, as evident by enhanced macropinocytosis, and changes to nucleic acid and lipid metabolism, which have been identified as potential therapeutic targets. Our goal is to understand the metabolic reprogramming in TSC, which may yield insights into the drivers of disease progression for clinical application. We hypothesize that AMLs in TSC patients show a distinct metabolic signature compared to those without AMLs. Methods: Utilizing the Tuberous Sclerosis Alliance Biosample Repository, we analyzed serum from 35 patients with TSC, confirmed by genetic testing. Concentrations of 276 metabolites were quantified in patients with AMLs (n = 18) and without AMLs (n = 17) using a LC/MS- based platform. We detected concentrations for 221 metabolites which were assessed using t-tests, and fold change (log2) analysis, to determine differentially abundant metabolites between TSC patients with or without AMLs. Statistical and pathway enrichment analyses were performed using MetaboAnalyst 6.0. Confirmatory t-tests were performed using PRISM. Results: 21 metabolites had greater than 2-fold (log2) change in serum concentration in AML vs. non-AML patients (17 increased, 4 decreased). We discovered that the endogenous metabolites picolinic acid (1.239, p=0.009), and ribulose 5-phosphate (1.432, p=0.003) levels were strongly increased in AML vs. non-AML patients. Pathway enrichment analysis showed that methylhistidine metabolism, and homocysteine metabolism showed increased metabolite saturation in patients with AMLs, compared to those without AMLs. Conclusions: Our data highlight the metabolic reprogramming that is characteristic of TSC and show that there are potential metabolic signatures intrinsic to TSC-associated AML tumorigenesis. Additional studies with larger patient cohorts may allow the development of prognostic indicators for formation of AMLs.