Background: In addition to Bevacizumab+Interferon, current treatment options of mRCC imply two major intracellular modes of action and thus classes of therapies: the four approved tyrosine kinase inhibitors (TKI) Sunitinib, Sorafenib, Pazopanib, Axitinib and the two inhibitors of the mammalian target of rapamycin (mTOR) Temsirolimus, Everolimus (EVE). With their availability efficacy of sequential treatment has become a central question of clinical research. While clinical trials recruit highly selected patients (pts) and usually focus on a single line of therapy, collected data of clinical registries may represent all patients and all sequential therapies. Methods: Starting in 12/2007 the registry aims to enrol a total of 1500 patients from more than 120 oncology and urology outpatient centres collecting data on all systemic treatments, outcome, patient and tumour characteristics. Here, the effectiveness of two 1^st – 2^nd-line sequential treatments, TKI–TKI vs TKI–EVE, was investigated with a multivariate cox proportional hazards model considering potential confounding variables (age, comorbidity, body mass index (BMI), duration of 1^st-line therapy, Motzer’s score and type of sequential treatment). Results: At the time of analysis, 481 pts had received sequential 1^st- and 2^nd-line treatment between 2007 and 2012. In total, 70% of pts received 1^st-line TKI-treatment. 46% of these pts received the sequential treatment TKI–TKI, 25% received TKI–EVE. In the multivariate analysis, high BMI (HR 0.946, 95% CI 0.9018-0.9923, p<.05) and a long duration of 1^st-line-therapy (HR 0.9967, 95% CI 0.9956-0.9979, p<.001) had a significant positive impact on OS, whereas high risk Motzer`s score (HR 8.9992, 95% CI 2.4231-33.4228, p<.01) had a significant negative impact on OS. However, the type of sequential treatment had no impact on OS (HR 1.0658, 95% CI0.6463-1.7576, p=0.802). Conclusions: The RCC Registry provides an overview of the current treatment reality in routine medical practice. TKI are the most frequently applied 1^st-line treatments, followed by TKI or mTOR inhibitors. Our data show no difference concerning the effectiveness of the sequential treatment TKI–TKI vs TKI–EVE.