Background: By the approval of new targeted agents in 2006, the standard of therapy in metastatic renal cell carcinoma (mRCC) changed, since they demonstrated significantly improved progression-free survival (PFS) rates compared with interferon in phase-3 clinical trials. Differences in overall survival (OS) could not be proven since many patients switched to another effective substance after progression of the disease. Thus, we compared two mRCC patient cohorts in order to detect OS differences between immunotherapy and targeted therapies in a real-life population outside controlled clinical trials. Methods: Clinico-pathological data from 594 mRCC patients, operated between 1984 and 2010 at a single tertiary academic center, were evaluated retrospectively with the null hypothesis, that there is no statistically significant difference in OS of patients treated either with interferon or targeted agents. Using electronical patient records, all data regarding the beginning, the duration, the lines and different forms of therapies were assessed. Patients’ cancer-specific survival (CSS), as well as OS were assessed using the Kaplan-Meier method, compared with the log-rank test. A first analysis revealed results for the entire study cohort. Subsequently, outcome analyses were restricted to mRCC patients with clear cell histology only. Results: With respect to the complete follow-up period, our results in both analyses did not show a statistically significant OS difference between the two therapy modalities. By limiting the observation period to 5 years after treatment initiation, a statistically significantly improved median five-year OS rate (26 mo.) for clear cell mRCC patients treated with targeted agents was observed, compared with 21 mo. in the interferon group (p= 0.028). Conclusions: Our results confirm the presumption of an improved OS in mRCC attributable to treatments with targeted agents compared with previous cytokine therapies.