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Purpose: Fumarate hydratase-deficient (FHdef) renal cell carcinoma (RCC) is a rare entity associated with the hereditary leiomyomatosis and RCC syndrome with no standard therapy approved. The aim of this retrospective study was to evaluate the efficacy of different systemic treatments in this population., Methods: We performed a multicentre retrospective analysis of Fhdef RCC patients to determine the response to systemic treatments. The endpoints were objective response rate (ORR), time-to-treatment failure (TTF), and overall survival (OS). The two latter were estimated using the Kaplan-Meier method., Results: Twenty-four Fhdef RCC patients were identified, and 21 under systemic therapy were included in the analysis: ten received cabozantinib, 14 received sunitinib, nine received "other antiangiogenics" (sorafenib, pazopanib, and axitinib), three received erlotinib-bevacizumab (E-B), three received mTOR inhibitors, and 11 received immune checkpoint blockers (ICBs). ORR for treatments were 50% for cabozantinib, 43% for sunitinib, 63% for "other antiangiogenics," and 30% for E-B, whereas ORR was 0% for mTOR inhibitors and 18% for ICBs. The median TTF (mTTF) was significantly higher with antiangiogenics (11.6 months) than with mTOR inhibitors (4.4 months) or ICBs (2.7 months). In the first-line setting, antiangiogenics presented a higher ORR compared with nivolumab-ipilimumab (64% versus 25%) and a significantly superior mTTF (11.0 months vs 2.5 months; p = 0.0027). The median OS from the start of the first systemic treatment was 44.0 months (95% confidence interval: 13.0-95.0)., Conclusions: We report the first European retrospective study of Fhdef RCC patients treated with systemic therapy with a remarkably long median OS of 44.0 months. Our results suggest that antiangiogenics may be superior to ICB/mTOR inhibitors in this population., Competing Interests: Conflict of interest statement E.C. has acted as a consultant and participated in advisory boards for Ipsen, BMS, Sanofi, and Tesaro et Pfizer. L.Cr. received honoraria from Janssen, Astellas, and Ipsen; and participated in advisory/consultancy for Ipsen, Janssen, and Astellas; and has received travel fees from Pfizer, Astellas, Ipsen, Novartis, and BMS. B.L. has acted as consultant and participated in advisory boards for and received travel support for participation in medical meetings from Sanofi, BMS, Bayer, Janssen, Pfizer, Novartis, and Merck. C.T. has participated in advisory boards from BMS, Pfizer, Pfizer, Ipsen, MSD, Astellas, Janssen, AstraZeneca, Merck, and Sanofi; has received travel fees from Pfizer, Sanofi, and AstraZeneca; and has received funding from AstraZeneca and Sanofi. G.V. reports consulting and advisory services and speaking/writing engagements for Pfizer, Novartis, Bayer, Merck, Roche, Ipsen, Astellas, Bristol-Myers Squibb, and MSD and research fees from Roche, Ipsen, and Pfizer outside the submitted work. C.S. received personal fees from Sanofi and BMS, as well as grants from Astellas, Pfizer and Ipsen, outside the submitted work. B.E. received grants from BMS, Novartis, and AVEO and personal fees from BMS, Aveo, Ipsen, Pfizer, Oncorena, Immunicum, Novartis, and Roche. L.A. received grants and honoraria from Pfizer, Novartis, BMS, Ipsen, Roche, AstraZeneca, Amgen, Astellas, Exelixis, Corvus Pharmaceuticals, Peloton therapeutics, MSD, and Merck, outside the submitted work. The rest of authors declare no conflicts of interest., (Copyright © 2021. Published by Elsevier Ltd.)