The reactivity of serum alpha-fetoprotein (AFP) from 20 patients with hepatocellular carcinoma (HCC) with immobilized lentil lectin was examined and found to be significantly greater (39% +/- 18%) than that of the same protein from seven patients with chronic liver disease (CLD, 11.2% +/- 3.3%), seven with fulminant hepatic failure (FHF, 10% +/- 8.4%), and eight normal pregnant women (4.1% +/- 2.7%). The reactivity with Concanavalin A (Con A) was also significantly greater for AFP from HCC patients (44.5% +/- 12.5%) than that from FHF patients (7.7% +/- 4%) and normal pregnant women (5.3% +/- 3.3%), but not from patients with CLD. The reactivity with lentil lectin permitted distinction between those with HCC (31.3% +/- 14.1%) and those with uncomplicated CLD (11.2% +/- 8.4%) even when the absolute levels of serum AFP were in the same range (80-400 ng/ml). Evaluation of the alterations by lectin binding methodology may be useful in overcoming problems associated with distinguishing between malignant and CLD, particularly at moderate serum AFP elevations.