INTRODUCTION: Polyamines, spermine and spermidine, are ubiquitous polycationic structures, which are essential for cell proliferation and differentiation. We tested whether spermine and spermidine could improve the prognostic ability of six established preoperative predictors of cancer-specific mortality (CSM) after partial or radical nephrectomy for renal cell carcinoma (RCC). MATERIALS AND METHODS: Overall, 385 patients with clinical stages T(1-3), M(0-1) RCC were treated with radical or partial nephrectomy at a single institution between 1990 and 2007. Kaplan-Meier plots depicted CSM after stratification according to spermine and spermidine levels (dichotomised to above and below the median value). Univariable and multivariable Cox regression models tested the prognostic ability of continuously coded spermine and spermidine levels in preoperative CSM predictions. Covariates consisted of pre-treatment T stage, M stage, age, gender and symptom classification. RESULTS: The 5-year CSM-free survival of patients with spermine levels < or =4.5 and >4.5 nmol/8x10(9) erythrocytes were, respectively, 79.5% and 65.0%. Similarly, the 5-year CSM-free survival of patients with spermidine levels < or =9.0 and >9.0 nmol/8x10(9) erythrocytes were, respectively, 81.1% and 63.7%. In multivariable analyses addressing CSM after surgery, both spermine (p< or =0.002) and spermidine (p< or =0.001) achieved independent predictor status and improved the accuracy of established preoperative CSM predictors by 2.1% (p<0.001). CONCLUSIONS: Circulating polyamine levels may significantly improve the prognostic value of established determinants of CSM in patients with RCC of all stages prior to nephrectomy. External validation of our findings is required prior to implementation in clinical practice.