Clear cell renal cell carcinoma (ccRCC), the most aggressive and lethal form of renal cell carcinoma accounts for over 90% of metastasis that occur following curative surgery for clinically confined disease. High relapse rates have prompted the evaluation of targeted therapies for the prevention or delay of metastatic disease in high-risk patients, with biomarkers offering significant potential to guide and improve patient management in this setting. In this current study we examined the value of the 4E-BP1/eIF4E axis for prognostic significance and risk stratification in patients with clinically confined ccRCC. This axis is a critical convergence point for many signalling pathways that are targeted by current therapies for the treatment of advanced RCC. Immunohistochemistry for phosphorylated 4E-BP1 (p4E-BP1) and total eIF4E was performed on tissue microarrays containing tumour cores from 135 patients with localised ccRCC. For both biomarkers 39% of all evaluable cores stained positive, with a strong correlation observed between the presence of p4E-BP1 and the overexpression of eIF4E within the same tumour (P = 0.005). Further, the combined expression of p4E-BP1 and eIF4E was associated with significantly worse disease-free survival of 2.9 vs 5.7 yrs compared to patients whose tumours expressed only one, or neither, of the biomarkers (P < 0.001). Cox-regression analysis confirmed the ability of the p4EBP1/eIF4E signature to independently identify high-risk patients with a Hazard Ratio of 4.2 (CI = 2.1-8.6; P < 0.001), compared to 3.3 for tumour grade 3 and 4, and 2.3 for tumour stage 3 and 4. These data show the powerful prognostic value of the p4E-BP1/eIF4E signature for potential management of patients with clinically confined ccRCC, and in addition provides insights into the possible key synergistic determinants of disease progression and treatment response.