The recurrence of hepatitis C virus (HCV) after orthotopic liver transplantation (OLT) is often associated with rapid fibrosis progression attributed to the state of impaired cellular immunity. At present, there are no means to predict those at risk for progression. Peripheral blood CD4+ adenosine triphosphate (ATP) release (the ImmuKnow assay) correlates with immunoreactivity and has been used to monitor global cellular immune function in transplant recipients. The aim of this study was to assess the relationship between cellular immune function measured by the ImmuKnow assay and fibrosis progression in patients with HCV recurrence after OLT. The ImmuKnow assay was prospectively performed in adult HCV patients at 4 and 12 months post-OLT. Protocol liver biopsies were performed (on day 7, in month 4, and yearly) after OLT. The first biopsy that showed fibrosis post-OLT was used to determine the time interval for developing fibrosis. Sixty-two patients met the inclusion criteria. The median follow-up time was 12 (6.5-12.1) months. Fibrosis progression was observed in 61.3% of the patients. ATP levels were lower in patients with fibrosis progression in comparison with patients without progression at 4 months (145 versus 259 ng/mL, P < 0.001) and at 12 months (152 versus 264 ng/mL, P = 0.008). ATP levels at 4 and 12 months post-OLT were found to be significantly associated with a higher hazard of progression. For each 25-unit increase in ATP levels at 4 and 12 months after transplantation, the hazard of fibrosis progression decreased by 22% (P = 0.001) and 12% (P = 0.015), respectively. In conclusion, greater suppression of cellular immunity, as measured by the ImmuKnow assay, is associated with more rapid progression of fibrosis in patients with recurrent HCV post-OLT. Post-OLT monitoring of CD4+ ATP activity may identify a subset of patients at greatest risk for early fibrosis progression. Liver Transpl 16:155–162, 2010. © 2010 AASLD.