Peripheral blood CD4+ adenosine triphosphate [ATP (ng/mL)] release [ImmuKnow Immune Cell Function Assay (ATP)] correlates to immunoreactivity. We hypothesized that ATP levels could provide insight into hepatitis C virus (HCV) infection and recurrent liver disease in liver transplantation (LT). We studied our center's LT cohort, in which ATP levels had been measured off protocol from February 2005 through July 2006. Of the 280 LTs performed since 1993, 114 (58.2%) fit the selection criteria, with a mean age of 49 ± 10 years. LT (alone/combination) indications included HCV (58%), alcoholic liver disease (41%), hepatocellular carcinoma (16%), and other (33%). Four hundred seventy-seven ATP levels were obtained: 3 (1-17) per patient 25 months (4 days to 19 years) from the time from transplantation. Final diagnoses were normal allograft function (n = 166, 35%), recurrent disease (n = 199, 42%), septic event (n = 34, 7%), other (n = 51, 11%), and undetermined (n = 27, 6%). Two hundred eighty-one ATP levels were obtained [3 (1-18) per patient] in 66 HCV(+) patients. Forty-five (68%) developed biopsy-proven recurrent liver disease [188/281 (67%) ATP levels]. The median ATP level (ng/mL) was 162 (1-761); it was lower in HCV(+) patients (151 ± 109) versus HCV(−) patients (211 ± 139; P < 0.0001). ATP ranges in HCV(+) patients were stable from the time from transplantation. In HCV(−) patients, ATP ranges were initially high and eventually decreased to HCV(+) levels (P = 0.01). Immunosuppressant levels were low in 62% of HCV(−) patients versus 38% of HCV(+) patients (P = 0.04). In HCV(+) patients, ATP was lower in disease recurrence (139 ± 97) versus none (181 ± 141; P = 0.01) with similar immunosuppression, and ATP decreased with grade (P = 0.05) but not stage. Time from transplantation, aspartate aminotransferase/alanine aminotransferase >1, and low ATP were independently associated with recurrent HCV. In conclusion, after LT, global cellular immune function appears depressed at baseline in HCV(+) patients versus HCV(−) patients and more so in HCV(+) recurrent disease. Liver Transpl 14:1313–1322, 2008. © 2008 AASLD.