Primary sclerosing cholangitis and autoimmune hepatitis are poorly-understood autoimmune liver diseases (ALD). Liver transplantation (Ltx) is the only treatment option once ALD progresses to end-stage liver disease. In ALD Ltx there is overlap in diagnostic findings for recurrent disease, rejection and biliary complications. There is an urgent need for a way to clearly distinguish alloimmune from autoimmune processes so that an appropriate diagnosis/treatment can be provided. We hypothesized that we could use high-throughput sequencing (HTS) of the TCR CDR3 β-chain to distinguish disease recurrence from allograft rejection after Ltx for ALD. We identified pre-transplant donor-reactive T cell clones (DRTCC) using the CFSE MLR method previously described (STM, Vol. 7, Issue 272, pp. 272ra10) and pre-transplant putative autoreactive T cell clones (ARTCC) by sequencing lymphocytes isolated from native liver. Using tissue resident memory T cell markers, we demonstrated very little contamination of the T cell population extracted from the native liver by circulating T cells. Unexpectedly, we found a predominance of ARTCC compared to DRTCC in post-transplant liver biopsies diagnosed as ACR in 3 ALD patients. In the post-transplant stool/bile for 1 patient there was a predominance of ARTCC. In conclusion, we are able to identify, characterize, and track ARTCC and DRTCC in post-transplant specimens of ALD Ltx recipients. The greater frequency of ARTCC than DRTCC in 3 patient biopsies diagnosed as ACR suggests that an autoimmune attack on the donor graft may be misdiagnosed as rejection in liver transplantation.