AIMS: Secreted frizzled-related protein (Sfrp)5 has beneficial effects on insulin sensitivity, inflammation and cardiovascular risk in different mouse models, but its relevance for cardiometabolic diseases in humans is controversial. We aimed to characterise associations of circulating SFRP5 with cardiometabolic risk factors and prediabetes/type 2 diabetes in a large population-based cohort. METHODS: Cross-sectional associations between serum SFRP5 and cardiometabolic risk factors as well as prediabetes/type 2 diabetes were investigated in 1096 participants aged 62-81 years from the German KORA F4 study, of whom 666 had prediabetes or type 2 diabetes. Multivariable linear regression models were adjusted for potential confounders including age, sex, body mass index (BMI), lifestyle factors, lipids, hypertension, kidney function and myocardial infarction. RESULTS: Higher serum SFRP5 levels were associated with lower HbA1c, BMI, systolic blood pressure, estimated glomerular filtration rate and high-sensitivity C-reactive protein levels and with higher levels of high-density lipoprotein cholesterol and adiponectin in the fully adjusted model (all P < 0.009). In contrast, favourable associations between SFRP5 and glycaemia, insulin, insulin resistance and other cardiometabolic risk factors were attenuated after adjustment for BMI. Serum SFRP5 levels were lower in participants with prediabetes or type 2 diabetes [(median (25th; 75th percentile) 48.8 (35.5; 65.7) ng/ml] compared to participants with normal glucose tolerance [55.9 (42.6; 69.6) ng/ml] (P < 0.001). In the fully adjusted model, higher SFRP5 was associated with lower odds of prediabetes/type 2 diabetes [OR (95% CI) (0.72 (0.58; 0.89)) per doubling of SFRP5, P < 0.01]. CONCLUSIONS: Higher serum SFRP5 was inversely associated with multiple risk factors for type 2 diabetes and cardiovascular diseases. However, BMI represents a strong confounder of some of these associations. Higher circulating SFRP5 was also associated with lower odds of prediabetes/type 2 diabetes, and this association was independent of BMI. Thus, SFRP5 emerges as novel biomarker that merits further research in the context of prevention of cardiometabolic diseases.