Acute cellular rejection (ACR) after liver transplantation occurs in as much as 70% of patients within the first year. There is very little known about ACR that occurs more than 1 yr after transplant, and it is generally believed that late occurring ACR may be more resistant to medical treatment and is associated with a higher rate of chronic ductopenic rejection and graft loss. A total of 532 recipients with more than 1000 d follow-up and who did not have hepatitis C were identified. Forty-three (8.1%) had biopsy proven late ACR at a mean of 1545 +/- 441 d post-transplant. Additionally, 38 of the 43 (88.4%) patients with late ACR had earlier episodes of ACR before 1000 d post-transplant vs. only 295 of the 488 patients (60.5%) that did not have late ACR (p < 0.01). The incidence of primary sclerosing cholangitis (PSC) was 32.6% among patients with late ACR and 11.1% among patients without late ACR (p < 0.01). The overall patient survival for patients who had late ACR (n = 43) is 81.4% while for patients without late ACR (n = 488) it is 82.0% (p = ns). Patients remain at risk for ACR even after 1000 d post-transplant, particularly those with PSC.