Background: Mammalian target of rapamycin (mTOR) inhibitors are approved in mRCC, but only a subset of patients derives clinical benefit. Recently, case reports have suggested that mutations in mTOR pathway genes might be associated with response to everolimus and temsirolimus in several malignancies, including mRCC. Methods: We amassed a large international cohort of mRCC patients with available tumor specimens who received mTOR inhibitors and had distinct clinical outcomes: responders were defined as complete response (CR), partial response (PR) or stable disease with any tumor shrinkage or no tumor growth for at least 6 months (R); non-responders were defined as disease progression within the first 3 months of therapy (NR). Tumor DNA from 94 patients was analyzed using a targeted next-generation sequencing panel covering 504 cancer genes. We performed a blinded analysis to investigate the correlation between mutations in mTOR pathway genes and response status. Results: Samples from 79 of 94 patients were successfully sequenced and were included in the analysis. Mutations are summarized in Table 1. Mutations in MTOR, TSC1 or TSC2 were more common in R (12/43) than NR (4/36) (OR: 3.05; p = 0.06; primary hypothesis). Similarly, mutations in TSC1 or TSC2 were more common in R (9/43) than NR (2/36) (OR: 4.42; p = 0.05; secondary hypothesis). In an exploratory analysis, 5/12 with PR/CR had mutations in MTOR, TSC1 or TSC2 vs 4/35 NR (OR: 5.28; p = 0.04). Conclusions: In this large cohort of mRCC patients, mutations in MTOR, TSC1 or TSC2 were more common in patients with clinical benefit from everolimus or temsirolimus than in NR. Mutations in those 3 genes were associated with PR/CR to mTOR inhibitors. In contrast, neither PTEN nor PIK3CA mutations showed any association with response. These findings suggest that a personalized medicine approach has value for selection of mTOR inhibitors in mRCC.