Background: The neutrophil-lymphocyte ratio (NLR) has been proposed as an indicator of systemic inflammation response and data from previous studies report controversial results about its independent prognostic role in non-metastatic renal cell carcinoma (RCC). Thus, we decided to evaluate the prognostic significance of NLR in a large cohort of RCC patients. Methods: Data from 843 consecutive non-metastatic RCC patients, operated with radical nephrectomy or nephron sparing surgery between 2000 and 2010 at a single tertiary academic center, were evaluated retrospectively. Pre-treatment NLR was calculated one day before surgical intervention. Patients were categorized according to a NLR cut-off value of 3.2. Cancer-specific–, metastasis-free–, as well as overall survival were assessed using the Kaplan-Meier method. To evaluate NLR’s independent prognostic significance, a multivariate Cox regression model was performed for all three endpoints. Results: An increased NLR was associated with several well established prognostic factors including tumor size, tumor grade, and histologic tumor necrosis (all p<0.05). Although an increased NLR was statistically significantly associated with poor outcome for all clinical endpoints (p<0.001), multivariate analysis identified an increased NLR as an independent prognostic factor for overall (HR=1.58, 95% CI=1.12-2.20, p=0.008), but not for cancer-specific (HR=1.55, 95% CI=0.89-2.70, p=0.116), nor for metastasis-free survival (HR=1.37, 95% CI=0.88-2.14, p=0.160). Conclusions: Risk prediction for cancer-related endpoints using NLR does not seem to add independent prognostic information to other well established prognostic factors in patients with non-metastatic RCC. Regarding patients’ overall survival, an increased NLR represented an independent risk factor, which might reflect a higher risk for cardiovascular, infectious, as well as for gastrointestinal morbidities and mortalities.