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Background: Measurement of alpha-fetoprotein (AFP) is widely used in diagnosing hepatocellular carcinoma (HCC). However, moderately elevated AFP levels are also found in patients with chronic liver diseases. Separated by isoelectric focusing, AFP isoforms appearing as Band + II have been found to be specific for HCC. Recently, the Band + II isoforms have been identified to be monosialylated AFP (msAFP), which has one sialic acid residue fewer than the predominant AFP isoforms associated with liver cirrhosis. The beta-galactoside alpha-2,6-sialyltransferase (ST2,6Gal I) is the key liver enzyme to transfer terminal sialic acid to the carbohydrate side chain of AFP. Methods: To investigate whether decrease of ST2,6Gal I expression and/or enzyme activity is the underlying cause for the formation of msAFP, serum sample, tumour and nontumour samples were collected from 19 HCC patients for the measurement of serum msAFP percentage, tissue ST2,6Gal I activity, and ST2,6Gal I mRNA. Results: Serum msAFP percentage was negatively correlated with absolute ST2,6Gal I activity in the tumour tissue (r = -0.423, P = 0.07) and with the percentage change of enzyme activity (r = -0.540, P < 0.02). Positively correlation between the enzyme activity and the mRNA level of ST2,6Gal I was found in nontumour tissues (r = 0.643, P < 0.01), but not in tumour tissues. Conclusion: These results suggest that decrease of ST6Gal I activity in tumours is a possible cause for the formation of HCC-specific hyposialylated AFP isoforms. In contrast to nontumour tissues, the down-regulation of the ST6Gal I activity in HCC may not be regulated at the transcription level. [ABSTRACT FROM AUTHOR]