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Background: Tetracyclines and clindamycin plus rifampicin combination therapy are both considered first-line therapy in current hidradenitis suppurativa guidelines. However, evidence for their efficacy is drawn from small studies, often without validated outcomes., Objective: To assess the 12-week efficacy of oral tetracyclines and a combination of clindamycin and rifampicin., Methods: A prospective, international cohort study performed between October 2018 and August 2019., Results: In total, 63.6% of the included 283 patients received oral tetracyclines, and 36.4% were treated with clindamycin and rifampicin. Both groups showed a significant decrease in International Hidradenitis Suppurativa Severity Score System from baseline (both P < .001). The Hidradenitis Suppurativa Clinical Response (HiSCR) was achieved in 40.1% and 48.2% of patients, respectively (P = .26). Patient characteristics or disease severity were not associated with the attainment of HiSCR or the minimal clinically important differences for the Dermatology Life Quality Index and pain., Limitations: Cohort study. Respectively, 23.9% and 19.4% of patients had to be excluded from the HiSCR analysis for the tetracycline and combination therapy group because of a low abscess and nodule count at baseline., Conclusion: This study shows significant efficacy of both tetracycline treatment and clindamycin and rifampicin combination therapy after 12 weeks in patients with hidradenitis suppurativa. No significant differences in efficacy were observed between the 2 treatments, regardless of disease severity., Competing Interests: Conflicts of interest Dr Tzellos has reported relationships with AbbVie, UCB, and Sanofi Genzyme. Dr Guillem has received honoraria from AbbVie and Novartis as a consultant and has given nonpaid lectures for AbbVie, Brothier, Cicaplus, Coloplast, Inresa, and Novartis. Dr Giamarellos-Bourboulis has received honoraria from Abbott CH, Angelini Italy, bioMérieux Inc, InflaRx GmbH, MSD Greece, and XBiotech Inc; independent educational grants from AbbVie, Abbott, Astellas Pharma Europe, AxisShield, bioMérieux Inc, InflaRx GmbH, ThermoFisher Brahms GmbH, and XBiotech Inc; and funding from the FrameWork 7 program HemoSpec (granted to the National and Kapodistrian University of Athens), the Horizon2020 Marie-Curie Project European Sepsis Academy (granted to the National and Kapodistrian University of Athens), and the Horizon 2020 European Grant ImmunoSep (granted to the Hellenic Institute for the Study of Sepsis). Dr Jemec has received honoraria from AbbVie, Chemocentryx, Coloplast, Incyte, Inflarx, Kymera, Leo Pharma, Novartis, and UCB for participation on advisory boards; grants from AbbVie, AstraZeneca, Inflarx, Janssen-Cilag, Leo Pharma, Novartis, Regeneron, and Sanofi for participation as an investigator; speaker honoraria from AbbVie, Boehringer Ingelheim, Galderma, and Novartis; and unrestricted departmental grants from Leo Pharma and Novartis. Dr Katoulis has reported relationships with AbbVie, Novartis, Genesis Pharma, Mylan, Janssen, Leo Pharma, and Lilly. Dr Koenig was an investigator, speaker, or advisor for AbbVie, Braun-Stiftung, and Celgene. Dr Lazaridou has received speaker honoraria, and/or honoraria for participation in advisory boards, and/or grants from AbbVie, Novartis, Genesis Pharma, Mylan, Pfizer, Janssen, Leo Pharma, Roche, Lilly, UCB, and Sanofi. Dr Matusiak reports personal fees from AbbVie, Amgen, Galapagos, InflaRx, Janssen-Cilag, LEO, Menlo, Novartis, Pfizer, Pierre Fabre, Regeneron, Trevi, and UCB. Dr Pinter has been an investigator, speaker, or advisor for AbbVie, Almirall-Hermal, Amgen, Biogen Idec, Biontec, Boehringer Ingelheim, Celgene, GlaxoSmithKline, Eli Lilly, Galderma, Hexal, Janssen, LEO-Pharma, MC2, Medac, Merck Serono, Mitsubishi, MSD, Novartis, Pascoe, Pfizer, Tigercat Pharma, Regeneron, Roche, Sandoz Biopharmaceuticals, Sanofi-Genzyme, Schering-Plough, and UCB Pharma. Dr Romani has reported relationships with AbbVie, Novartis, Leo Pharma, Janssen, Almirall, and Isdín. Dr Saunte was paid as a consultant for advisory board meeting by AbbVie, Janssen, Sanofi, and Leo Pharma and received speaker honoraria and/or grants from AbbVie, Pfizer, Galderma, Novartis, and Leo Pharma during the last 5 years. Dr Szepietowski reports personal fees from AbbVie, Amgen, Galapagos, InflaRx, Janssen-Cilag, LEO, Menlo, Novartis, Pfizer, Pierre Fabre, Regeneron, Sandoz, Sanofi, Sienna, Trevi, and UCB. Dr Trigoni has reported relationships with AbbVie, UCB, Novartis, and LEO. Dr Trigoni has reported relationships with AbbVie, UCB, Novartis, and LEO. Dr van der Zee has received honoraria from AbbVie. Drs van Straalen, Benhadou, Cuencia-Barrales, Daxhelet, Daoud, Efthymiou, Marzano, Molina-Leyva, Moltrasio, Potenza, Skroza, Stergianou, and Vilarrasa have no conflicts of interest to declare., (Copyright © 2021 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)