Background: The VEGFR-TKIs Sunitinib and Pazopanib are the currently recommended 1^st line agents for the treatment of renal cell carcinoma (RCC). Everolimus is a well-established treatment option after failure of a prior VEGFR-TKI. However, few prospective clinical data exist on the efficacy and safety of Everolimus after failure of a single line of VEGFR-TKI therapy and no clinical data exists on the efficacy and safety of Everolimus following Pazopanib treatment. Methods: This phase IV clinical trial investigated Everolimus 10 mg daily in patients who have progressed on or after 1^st line treatment with Sunitinib or Pazopanib. Adult patients with advanced clear cell RCC and an ECOG 0-1 were included. The primary endpoint was the rate of patients progression-free after 6 months of treatment. Results: 16 and 13 patients who received prior Sunitinib and Pazopanib, respectively, have been enrolled at 13 German sites. The median age was 65 years in the Sunitinib (SUN) group and 74 years in the Pazopanib (PAZ) group. After 6 months of Everolimus treatment, 11/12 (92%) patients in the SUN group showed disease progression, whereas 6/13 (46%) patients in the PAZ group remained progression-free (FAS population). The median OS was 14.8 months in the SUN group (95% CI 9.4 – not reached (NR)) and 20.4 months in the PAZ group (95% CI 11.7 – NR). The most common adverse events (AE) regardless of any relation to study drug included anemia (31.1% (SUN group) vs. 53.8% (PAZ group)), nausea (25.0 vs. 46.2%), stomatitis (12.5 vs. 61.5%), peripheral edema (12.5 vs. 53.8%), and dyspnea (12.5 vs. 46.2%). Conclusions: Patients in the PAZ group showed a lower rate of tumor progression within 6 months and a longer PFS as compared to the SUN group. The results confirm Everolimus as an effective 2nd line treatment option with a favorable safety profile, especially following Pazopanib, and the sequence Pazopanib - Everolimus as effective treatment option for mRCC patients. However, due to the small number of patients enrolled in the study, results have to be interpreted with caution. The types of observed AE are consistent with the well-known toxicity profile of Everolimus. Clinical trial information: NCT01514448