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Objectives To determine if liver cirrhosis is associated with reduced efficacy of insulin-glucose treatment in moderate to severe hyperkalaemia. Design Retrospective, cohort study. Setting Two secondary and one tertiary care hospital at a large metropolitan healthcare network in Melbourne, Australia. Participants This study included 463 adults with a mean age of 68.7+/-15.8 years, comprising 79 patients with cirrhosis and 384 without cirrhosis as controls, who received standard insulin-glucose treatment for a serum potassium >=6.0 mmol/L from October 2016 to March 2020. Patients were excluded if they received an insulin infusion, or if there was inadequate follow-up data for at least 6 hours after IDT due to death, lost to follow-up or inadequate biochemistry monitoring. The mean Model for End-stage Liver Disease score in patients with cirrhosis was 22.2+/-7.5, and the distribution of the Child-Pugh score for cirrhosis was: class A (24%), class B (46%), class C (30%). Outcome measures The primary outcome was the degree of potassium lowering and the secondary outcome was the proportion of patients who achieved normokalaemia, within 6 hours of treatment. Results The mean pretreatment potassium for the cohort was 6.57+/-0.52 mmol/L. After insulin-glucose treatment, mean potassium lowering was 0.84+/-0.58 mmol/L in patients with cirrhosis compared with 1.33+/-0.75 mmol/L for controls (p<0.001). The proportion of patients achieving normokalaemia was 33% for patients with cirrhosis, compared with 53% for controls (p=0.001). By multivariable regression, on average, liver cirrhosis was associated with a reduced potassium lowering effect of 0.42 mmol/L (95% CI 0.22 to 0.63 mmol/L, p<0.001) from insulin-glucose treatment, after adjusting for age, serum creatinine, cancer, pretreatment potassium level, beta-blocker use and cotreatments (sodium polystyrene sulfonate, salbutamol, sodium bicarbonate). Conclusions Our observational data suggest reduced efficacy of insulin-glucose