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Background and Aims: Metformin is an oral anti-hyperglycemic recommended by the American Diabetes Association (ADA) as a preferred initial pharmacologic agent for type 2 diabetes. Metabolic acidosis is a rare yet severe side effect of it. We examined the association of metformin use and dosage on the risk of metabolic acidosis in diabetic patients with different degrees of chronic hepatitis B (CHB)-related cirrhosis and chronic kidney disease (CKD)., Methods: Metabolic acidosis was defined by blood pH ≤7.35, together with lactate >5 mmol/L or arterial bicarbonate ≤18 mmol/L or venous bicarbonate ≤21 mmol/L, and/or diagnosis codes. Child-Pugh class and CKD stage were included in the model as time-dependent covariates. Age, gender, comorbidities, and use of relevant medications were adjusted as covariates. Maximum daily dose of metformin was classified into ≤1000 mg and >1000 mg., Results: We identified 4431 diabetic patients with CHB-related cirrhosis between 2000 and 2017 from a territory-wide database in Hong Kong. The risk of metabolic acidosis increased with Child-Pugh class B and C cirrhosis regardless of CKD stage (adjusted subdistribution hazard ratio [aSHR] ranged from 3.50 to 86.16). Metformin use was associated with a higher risk in patients with Child-Pugh class B or C cirrhosis and stage 3A CKD or above (aSHR ranged from 1.55 to 2.46). In stage 4/5 CKD, a daily dose of metformin ≤1000 mg was still associated with a higher risk of metabolic acidosis regardless of the severity of cirrhosis (aSHR ranged from 2.45 to 3.92)., Conclusion: In conclusion, patients with Child-Pugh class B cirrhosis or above were at a higher risk of metabolic acidosis. Metformin further increased the risk in patients with Child-Pugh class B cirrhosis or above and stage 3A CKD or above. Dose adjustment in stage 4/5 CKD did not reduce the risk of metabolic acidosis., Competing Interests: Terry Yip has served as an advisory committee member and a speaker for Gilead Sciences. Vincent Wong has served as an advisory committee member for 3V‐BIO, AbbVie, Allergan, Boehringer Ingelheim, Echosens, Gilead Sciences, Intercept, Janssen, Novartis, Novo Nordisk, Perspectum Diagnostics, Pfizer, TARGET‐NASH, and Terns; and a speaker for Bristol‐Myers Squibb, Echosens, Gilead Sciences, and Merck. He has also received a research grant from Gilead Sciences. Henry Chan is an advisor for AbbVie, Aptorum, Arbutus, Hepion, Intellia, Janssen, Gilead, GSK, GRAIL, Medimmune, Merck, Roche, Vaccitech, VenatoRx, Vir Biotechnology; and a speaker for Mylan, Gilead, and Roche. Grace Wong has served as an advisory committee member for Gilead Sciences, as a speaker for Abbott, Abbvie, Bristol‐Myers Squibb, Echosens, Furui, Gilead Sciences, Janssen, and Roche, and received research grant from Gilead Sciences. The other authors declare that they have no competing interests., (© 2021 The Authors. Health Science Reports published by Wiley Periodicals LLC.)