Background: Serum hyaluronic acid and biochemical models which require hyaluronic acid analysis are commonly used as predictors of liver fibrosis in patients with chronic liver disease, however biological variation data for hyaluronic acid are deficient. Methods: Four serial serum samples were obtained at weekly intervals from healthy volunteers and patients with chronic hepatitis B, chronic hepatitis C and nonalcoholic fatty liver disease (NAFLD; 20 in each group). The within-individual week-to-week variation (CVI ) and reference change values for hyaluronic acid, α2 -macroglobulin and Hepascore were obtained. Hepascore is calculated from hyaluronic acid, α2 -macroglobulin, bilirubin and γ -glutamyltransferase activity. Results: Hyaluronic acid displayed large within-individual variation, the CVI values were 62% in healthy subjects, 38% in hepatitis C, 37% in hepatitis B and 36% in NAFLD patients. Hepascore CVI s were 43% in healthy subjects, 24% in hepatitis C, 28% in hepatitis B and 39% in NAFLD patients. α2 -Macroglobulin was much less variable with CV I s ranging from 4.4% to 7.6%. Bland-Altman plots of week-to-week variations showed rates of significant disagreement for samples collected in any 2 successive weeks varied from 5% in NAFLD patients to 8.3% in healthy subjects. Conclusions: When using non-fasting serum samples, hyaluronic acid and to a lesser extent, the Hepascore model display large within-individual variations in both health and chronic liver disease. This information is critical for interpreting the significance of both single measurements and changes in serial measurements.