The serum levels of soluble beta2-mu-associated and beta2-mu-free HLA class I heavy chains were determined in 28 interferon-alpha nonresponder chronic hepatitis C patients retreated with interferon-alpha plus ribavirin and in 70 healthy subjects. The baseline levels of beta2-mu-associated and beta2-mu-free HLA class I heavy chains were significantly higher in patients than in healthy controls (P = 0.001). The levels of beta2-mu-associated HLA class I heavy chains significantly increased in responder patients with respect to nonresponders at the third month of treatment (P = 0.03). At the sixth month of treatment and after 6 months of follow up the levels of beta2-mu-associated HLA class I heavy chains decreased in responder patients and increased in nonresponders. The levels of beta2-mu-free HLA class I heavy chains showed only minor changes during and after treatment. We suggest that the determination of hepatitis C virus RNA levels combined with soluble beta2-mu-associated HLA class I heavy chains, as a marker of immune activation, could identify interferon-alpha non responder chronic hepatitis C patients most likely to respond to a retreatment with interferon-alpha plus ribavirin.