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Background: Guselkumab is an interleukin (IL)-23 pathway blocker with proven efficacy in patients with moderate-to-severe plaque psoriasis. Early intervention with guselkumab may result in changes to the clinical disease course versus later intervention., Methods and Analysis: Here we present the rationale and design of a phase 3b, randomised, double-blind, multicentre study (GUIDE), comparing treatment effects of guselkumab in patients with short (≤2 years) or longer (>2 years) duration of plaque-type psoriasis, measured from first appearance of psoriatic plaques. Participants achieving skin clearance (Psoriasis Area and Severity Index (PASI)=0) by week 20 and maintaining complete clearance at week 28 visit ('super-responders' (SRe)) will be randomised to continue approved maintenance dosing every 8 weeks (q8w) versus an investigational maintenance dosing interval of 16 weeks (q16w) until week 68. Primary endpoint: proportion of participants in the q8w vs q16w arms with absolute PASI <3 at week 68. Participants with PASI <3 at week 68 will be withdrawn from guselkumab treatment for up to 48 weeks. Participants not achieving SRe criteria (non-SRe) will remain in the study with q8w guselkumab dosing through week 68. Additional to serum samples obtained from all patients, skin biopsies and whole-blood samples will be taken from SRe and non-SRe participants at various time points in optional substudies. Analyses include: genetics; immunophenotyping (fluorescence-activated cell sorting); gene and protein expression profiling; immunohistology. By merging clinical endpoints with mechanistic findings, this study aims to elucidate how IL-23 blockade with guselkumab can modify the disease course by altering molecular and cellular drivers that cause relapse after treatment withdrawal, particularly among SRe., Ethics and Dissemination: Approval obtained from ethics committee Medical Council Hamburg, Germany (PVN5925). GUIDE is compliant with the Declaration of Helsinki., Trial Registration Number: Registered at ClinicalTrials.gov (NCT03818035). All primary endpoint results (prespecified analyses) will be submitted to peer-reviewed, international journals within 18 months after primary completion date., Competing Interests: Competing interests: KE reports grants and personal fees from Janssen during the conduct of the study, grants from AbbVie, LEO Pharma, UCB and Novartis, and personal fees from AbbVie, Almirall, BMS, LEO Pharma, Lilly, Sanofi, UCB, Galderma and Novartis outside the submitted work; PW reports receiving honoraria as consultant or speaker from the following companies involved in the development or distribution of drugs for psoriasis: AbbVie, Almirall, Biogen, Celgene, Eli Lilly, Janssen, LEO Pharma, Medac and Novartis, and honoraria received by his institution for active participation in clinical studies sponsored by Janssen, AbbVie and Eli Lilly; AP has no conflicts of interest to report; KS reports conducting clinical studies during the past 36 months with the following companies: AbbVie, Almirall, Boehringer, Celgene, Chugai, Galapagos, Galderma, Janssen-Cilag, LEO Pharma, Lilly, Merck Sharp & Dohme Corp., Novartis Regeneron and UCB Pharma; KA reports honoraria for participation in advisory boards, consultation, clinical trials or as speaker from AbbVie, Almirall, Antabio, Bayer, BMS, Euroimmune, Emphasis, Emeritipharma, Galderma, Janssen, La Roche-Posay, LEO Pharma, L’Oréal, Novartis, Parexel International, Pierre Fabre, Roxall, RG, Sanofi Genzyme, TFS Trial Form Support and UCB; SW is a full-time employee of Janssen-Cilag Germany; EJM-E is a full-time employee of Johnson & Johnson, and is listed as an inventor on a patent application related to uses of guselkumab to treat psoriasis, pending; HB reports personal fees from Janssen-Cilag Germany during the conduct of the study, and personal fees from Janssen-Cilag Germany outside the submitted work; FJHT reports personal fees from Janssen-Cilag, Germany during the conduct of the study and personal fees from Janssen-Cilag, Germany outside the submitted work; KR reports grants and personal fees from Janssen during the conduct of the study, grants from AbbVie, Lilly, LEO Pharma, UCB, Pfizer, Affibody, Biogen-Idec, Boehringer Ingelheim Pharma, BMS, Celgene, Covagen, Forward Pharma, Fresenius Medical Care, Galapagos, Kyowa Kirin, Medac, Merck Sharp & Dohme, Milteny, Novartis, Ocean Pharma, Sandoz, Sanofi, Sun Pharma, Takeda and XBiotech; personal fees from AbbVie, Lilly, LEO Pharma, UCB, Pfizer, Amgen, Affibody, Biogen-Idec, Boehringer Ingelheim Pharma, BMS, Celgene, Covagen, Forward Pharma, GSK, Kyowa Kirin, Medac, Merck Sharp & Dohme Corp, Novartis, Ocean Pharma, Samsung Bioepis, Sandoz, Sanofi, Takeda, Valeant and Xenoport outside the submitted work., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)