We compared the results of HFE genotype with tests for iron binding saturation (IBS) in 190 consecutive patients with liver disease using 2 IBS cutoff levels: 45% and 60%. Saturation was more than 45% in 117 patients (61.6%) and more than 60% in 89 (46.8%). The number of patients (10) with the highest-risk HFE genotype (C282Y homozygote) was higher than expected. Elevated IBS cannot be used to predict genotype. There was a modest association of C282Y homozygosity with increased IBS (7 of 10, saturation >45% and 6 of 10, >60%). There was poor correlation of elevated saturation with other genotypes containing 1 or more HFE variants. Patients with a wild-type genotype (lacking HFE variants) and elevated IBS were far more likely to have an iron binding capacity less than 250 microg/dL (<44.8 micromol/L) than those with saturation values less than 45%, suggesting that a significant percentage of elevated IBS test results in liver disease are false-positives associated with decreased synthetic capacity. Nevertheless, an appreciable number of patients with elevated IBS had normal iron binding capacity, indicating the complexity of relationships among iron absorption and binding, disease status, HFE genotype, and other potential modifying factors in liver disease.