IMPORTANCE Randomized controlled trial protocols form the basis for study planning, conduct, reporting, and external review (peer review). However, the completeness of trial protocols varies, and important elements of trial design and conduct are often not considered. This SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) statement aims to improve the completeness of trial protocols. The SPIRIT guidance was first published in 2013. To ensure that this guidance remains useful to users, it requires periodic revision to incorporate the latest evidence and best practices. OBJECTIVE To systematically revise the SPIRIT recommendations regarding the minimum requirements that should be addressed in randomized controlled trial protocols. DESIGN We have completed a scoping review and compiled project-specific recommendations summarizing empirical and theoretical evidence. We developed a database of potential changes to the SPIRIT 2013 checklist and compiled a list of potential changes. This list was enriched with recommendations from lead authors of existing SPIRIT/CONSORT (Consolidated Standards of Reporting Trials) extensions (Harms, Outcomes, and Non-Pharmacological Treatments) and other reporting guidance (TIDieR). Potential changes were ranked using three Delphi surveys followed by a consensus conference. FINDINGS In total, 317 individuals participated in the Delphi consensus process, and 30 experts attended the consensus conference. This process resulted in the addition of two new protocol items, the revision of five items, and the deletion/merging of five items. Key sections from other relevant reporting guidelines have been integrated. Notable changes include a new section on open science, an emphasis on harm assessment and description of interventions and comparators, and a new section on how patients and the public should be involved in the design, conduct, and reporting of trials. The SPIRIT 2025 statement consists of an evidence-based checklist outlining 34 minimum items that should be addressed in a trial protocol and a diagram illustrating the timeline for participant enrollment, intervention, and evaluation. To facilitate implementation, we have also developed an expanded version of the SPIRIT 2025 checklist and accompanying explanatory and detailed documentation. CONCLUSIONS AND RELEVANCE Wide support for and adherence to the revised SPIRIT 2025 Statement has the potential to increase the transparency and integrity of trial protocols for researchers, trial participants, patients, funders, research ethics committees, journals, trial registries, policymakers, regulators, and peer reviewers.