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Background: Clinically significant liver fibrosis is associated with future adverse events in patients with steatotic liver disease. We designed a software tool for detection of clinically significant liver fibrosis in primary care., Methods: In this prospective cohort study, we developed and validated LiverPRO using six independent cohorts from Denmark, Germany, and England that included patients from primary and secondary care with steatotic liver disease related to alcohol or metabolic dysfunction. We used clinically significant fibrosis (histology stage ≥F2) and advanced fibrosis (≥F3) as outcomes for variable selection in the development cohort and built the model with fractional polynomial regression. In all cohorts, we independently validated the tool for prediction of elevated liver stiffness by transient elastography (≥8 kPa and ≥12 kPa) and for the 2-year and 5-year risk of liver-related events. Diagnostic performance was assessed using the area under the receiver operating curve (AUC), with clinical performance evaluated through sensitivity, specificity, and Harrell's C-statistic for prognostic purposes., Findings: In the development cohort (n=462), we derived 466 multivariable models consisting of age in combination with three to nine variables from a list of nine blood tests (aspartate aminotransferase, alkaline phosphatase, gamma-glutamyl transferase, international normalised ratio, albumin, sodium, bilirubin, platelet count, and cholesterol). In the development cohort, LiverPRO diagnosed clinically significant fibrosis with good accuracy (transient elastography ≥8 kPa area under the receiver operating characteristic curve [AUC] 0·86 [95% CI 0·83-0·90]). In the DECIDE validation cohort (n=6468), LiverPRO detected participants with a transient elastography of 8 kPa or higher with good accuracy (AUC 0·80 [95% CI 0·78-0·82]), comparable to enhanced liver fibrosis testing (0·78 [0·75-0·80]) and the LiverRisk score (0·81 [0·79-0·84]), but superior to the Fibrosis-4 index (0·69 [0·66-0·72]) and NAFLD Fibrosis Score (0·74 [0·72-0·77]). Findings were consistent in three other validation cohorts (n=2554), albeit accuracy was slightly lower. Using a rule-out cutoff of less than 25% (indicating no further examinations required), LiverPRO had a rule-out sensitivity of 80·6% (95% CI 76·4-84·3) and a rule-out negative predictive value of 98·0% (95% CI 97·5-98·4) in the DECIDE cohort. Similarly, with a rule-out cutoff of less than 1·3, FIB-4 had a rule-out sensitivity of 53·8% (48·5-58·9) and a rule-out negative predictive value of 95·8% (95·1-96·4). For rule-in thresholds, using a cutoff of more than 65% (indicating referral to a hepatologist required) LiverPRO had a rule-in specificity of 95·5% (95% CI 94·9-96·0) and a rule-in positive predictive value of 33·0% (95% CI 28·5-37·8) in the DECIDE cohort whereas FIB-4, with a rule-in threshold of 2·67, had a rule-in specificity of 98·7% (94·9-96·0) and a rule-in positive predictive value 35·6% (27·0-44·9). Using UK Biobank data, LiverPRO predicted liver-related events with a C-statistic of 0·80 (0·77-0·84) at 2 years., Interpretation: LiverPRO reliably identifies clinically significant liver fibrosis and elevated liver stiffness, predicts the risk of liver-related events in primary care, and is adaptable to the availability of different liver blood test analytes. On the basis of these results LiverPRO was certified according to IVDR class b, obtaining European CE approval in 2024., Funding: EU Horizon 2020 research and innovation programme and Novo Nordisk Foundation., Competing Interests: Declaration of interests KL, MT, and AK are founders of the spin-out company Evido, which holds a commercial license with the University of Southern Denmark to use the invention LiverPRO commercially. KL has received speaker fees from Siemens Healthcare and Novo Nordisk. MK has received speakers fees from Siemens. MT has received speaker fees from GSK, Echosens, Norgine, Siemens Healthcare, Takeda, Madrigal, and Tillotts Pharma, and advisory fees from GE Healthcare, GSK, AstraZeneca, Boehringer Ingelheim, and Novo Nordisk. MT also serves as a board member for Alcohol & Society (non-governmental organisation) and a board member and co-founder of Evido. AK has served as speaker for Novo Nordisk, Norgine, Siemens, and Nordic Bioscience, and participated in advisory boards for Norgine, Siemens, Resalis Therapeutics, Boehringer Ingelheim, and Novo Nordisk, all outside of the submitted work. AK declares research support from Norgine, Siemens, Nordic Bioscience, Astra, and Echosens. AG served as a steering committee member or advisor for AbbVie, Alexion, Bayer, BMS, Eisai, Falk, Gilead, Heel, Intercept, Ipsen, Merz, MSD, Novartis, Pfizer, Roche, and Sanofi-Aventis and is a speaker for AbbVie, Advanz, Alexion, BMS, Burgerstein, CSL Behring, Falk, Gilead, Intercept, Merz, MSD, Novartis, Novo Nordisk, and Roche. He has received research support from Intercept and Falk (both NAFLD CSG), and Novartis. HW declares honoria for consulting and speaking from AstraZeneca and honoria from Abbott, Falk, Gilead Sciences, GSK, Intercept/Advanz, and Roche. IG has received ISCIII and Pfizer grants. PG has received research funding from Gilead and Grifols. PG consulted or attended advisory boards for Gilead, RallyBio, SeaBeLife, Merck, Sharp and Dohme (MSD), Ocelot Bio, Behring, Roche Diagnostics International, and Boehringer Ingelheim, and declares speaker fees from Pfizer. TH has received research support from Novo Nordisk. CDH has received speaker fees from Novo Nordisk. JKH has received speaker fees from Norgine. SZ has received consulting fees from BioMarin, Gilead, AbbVie, and Novo Nordisk, and speakers fees from AbbVie, Gilead, and MSD. MI has received travel support from Novo Nordisk. CB has Novo Nordisk stocks. KB, KT, SJ, MB, SM, NG, SD, NT, LLK, HLS, KSB, RH and PA declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)