The objective of this study was to analyze the expression levels of multiple components in the mammalian target of rapamycin (mTOR) signaling pathway in radical nephrectomy specimens from patients with metastatic renal-cell carcinoma (RCC) treated with mTOR inhibitors in order to identify factors predicting susceptibility to these agents. This study retrospectively included a total of 48 consecutive patients undergoing radical nephrectomy, who were diagnosed with metastatic RCC and subsequently treated with an mTOR inhibitor (everolimus or temsirolimus) as either first- or second-line systemic therapy. Expression levels of 5 molecular markers involved in the signaling pathway associated with mTOR, including PTEN, phosphorylated (p)-Akt, p-mTOR, p-p70 ribosomal S6 kinase, and p-4E-binding protein 1 (4E-BP1), were measured by immunohistochemical staining of primary RCC specimens. Of several factors examined, bone metastasis, liver metastasis, and the expression level of p-4E-BP1 were shown to have significant impacts on the response to the mTOR inhibitors. Progression-free survival (PFS) was significantly correlated with the expression levels of PTEN and p-4E-BP1 in addition to the presence of bone metastasis on univariate analysis. Of these significant factors, p-4E-BP1 expression and bone metastasis appeared to be independently associated with PFS on multivariate analysis. These findings suggest that it would be useful to consider the expression levels of potential molecular markers in the mTOR signaling pathway, particularly p-4E-BP1, as well as conventional clinical parameters when selecting patients with metastatic RCC who are likely to benefit from treatment with mTOR inhibitors.