Previous studies from this laboratory support the view that increased serum ferritin levels are associated with an increased risk of primary hepatocellular carcinoma (PHC). We have tested this hypothesis in a population of Korean patients with chronic liver disease followed for development of PHC. Serum ferritin levels were measured over time in 249 patients with liver diseases (mostly chronic) followed for 2 to I7 years in Seoul, Korea. Most of the patients were chronically infected with hepatitis B virus. During the first 8 months of follow-up, there were no cases of PHC and no deaths. During this same period, no patient had a serum ferritin level initially below 300 ng/ml and rising above 300 ng/ml, but some patients with ferritin levels above 300 nglml experienced decreases to below 300 ng/ml. Therefore, patients were grouped by ferritin level during the first 8 months of follow-up into 3 categories according to the above criteria. Multivariate analysis showed that consistently elevated ferritin levels (category 3) were significantly associated with the development of PHC. Men were more likely to have elevated ferritin levels than women and were at higher risk of developing PHC. Men who were chronically infected with HBV and had ferritin levels above 300 nglml had a 50% chance of developing PHC during the follow-up period, compared with a 20% risk of PHC for men with lower ferritin levels (categories I and 2). This elevated risk of PHC in men with elevated ferritin levels was confined to the first 3 years of follow-up.