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We describe repeated episodes of hepatitis C (HCV) activation associated with initiation of highly active antiretroviral therapy (HAART) in two HIV/HCV coinfected individuals with undetectable serum HCV RNA. Both patients developed high HCV viremia (>1 million IU/mL) and elevations in aminotransferases >10 times upper limit of normal) within 4 months of starting HAART. This is the first report of clinically significant HCV activation in HCV-seropositive patients with initially undetectable HCV viremia. These observations suggest that flares of hepatitis C in the setting of the immune reconstitution inflammatory syndrome can occur even in those patients who have undetectable serum HCV levels prior to HAART initiation. [ABSTRACT FROM AUTHOR]