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Background: Sarcomatoid differentiation/histology of renal cell carcinoma (sRCC) in patients with metastatic renal cell carcinoma (mRCC) is still underresearched in current therapy regimes. We aimed to evaluate the impact of sRCC on outcomes in patients with mRCC treated with tyrosine kinase inhibitors (TKIs). Methods: We collected complete data of 262 consecutive mRCC patients from our institutional database for this retrospective study. All patients were treated with TKIs within a single or multimodal treatment approach. All analyses were adjusted for the presence of sRCC. Descriptive statistics as well as uni- and multivariable outcome metrics, including progression-free (PFS) and overall survival (OS) as endpoints were performed. Results: Overall, 18 patients had sRCC (6.9%). Patients with sRCC had more often clear-cell histology ( p = 0.047), a higher T-stage ( p = 0.048), and underwent cytoreductive nephrectomy more frequently ( p < 0.001). The most common first-line TKIs were Sunitinib (65.6%), Sorafenib (19.5%), and Pazopanib (10.3%), respectively. At a median follow-up of 32 months, patients with sRCC had significantly reduced PFS ( p = 0.02) and OS ( p = 0.01) compared to patients without sRCC. In multivariable analyses that adjusted for the effects of standard mRCC predictors, the sarcomatoid feature retained its independent association with inferior PFS (HR: 2.39; p = 0.007) and OS (HR: 2.37; p = 0.001). This association remained statistically significant in subgroup analyses of patients with Sunitinib as first-line therapy (PFS p < 0.001; OS: p < 0.001). Conclusion: Despite its rare occurrence, our findings confirm sRCC as a powerful predictor for inferior outcomes in mRCC treated with targeted therapies. This suggests a need for more tailored treatment strategies in patients harboring mRCC with sarcomatoid histology to improve oncological outcomes., Competing Interests: SFS is consulting or advising the following: Astra Zeneca, BMS, Ferring, Ipsen, Jansen, MSD, Olympus, Pfizer, Pierre Fabre, Richard Wolf, Roche, Sanochemia, and Urogen. MR is a speaker for Bayer Healthcare, Bristol Myer Squibb, EUSA Pharma, IPSEN Pharma, Novartis, Roche, and Pfizer. MR is a consultant and/or received honoraria by Bayer Healthcare, Bristol Myer Squibb, IPSEN Pharma, MSD, Novartis, Roche, and Pfizer. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor declared a shared affiliation with one of the authors, SFS, at the time of review., (Copyright © 2021 Janisch, Kienapfel, Fühner, Klotzbücher, Marks, Hillemacher, Meyer, Iwata, Parizi, Sauter, Fisch, Shariat, Dahlem and Rink.)