Objective: This article describes the statistical analysis plan for the Biomarker-guided intervention to prevent AKI after major surgery (BigpAK-2) trial. Design: Adaptive trial design with an interim analysis after enrolment of 618 evaluable patients. Setting: The BigpAK.-2 trial is an international, prospective, randomised controlled multicentre study. Participants: The BigpAK-2 study enrols patients after major surgery who are admitted to the intensive care or high dependency unit and are at high-risk for postoperative AKI as identified by urinary biomarkers (tissue inhibitor of metalloproteinases-2 and insulin-like growth factor binding protein 7 ([TIMP-2]∗[IGFBP7]) will be enrolled. Intervention: Patients are randomly and evenly allocated to standard of care (control) group or the implementation of a nephroprotective care bundle (intervention group), as recommended by the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines. The KDIGO care bundle recommends discontinuation of nephrotoxic agents if possible, ensuring adequate volume status and perfusion pressure, considering functional haemodynamic monitoring, regular monitoring of serum creatinine and urine output, avoiding hyperglycemia, and considering alternatives to radiocontrast procedures when possible. Results: The BigpAK-2 study investigates whether the biomarker-gudied implementation of the KDIGO care bundle reduces the incidence of moderate or severe AKI (stage 2 or 3), according to the KDIGO 2012 criteria, within 72 h after surgery. Conclusion: AKI is a common and often severe complication after major surgery. As no specific treatments exist, prevention of AKI is of high importance. The BigpAK-2 study investigates a promising approach to prevent AKI after major surgery. Trial registration: The trial was registered prior to start at clinicaltrials.gov; NCT04647396.