Abstract Background: Thyroid hormone (T3) and its receptor (TR) are involved in cell metabolism and cancer progression. Hypothyroidism is a significantly elevated risk factor for hepatocellular carcinoma (HCC). Alpha-fetoprotein (AFP) is increased in the majority of patients with HCC and may be useful in the diagnosis and follow-up of cases of HCC. The relationship between T3/TR and AFP levels in HCC is still unclear. Design: We used microarrays to compare expression profiles of lncRNAs in HepG2-TRα1 cells treated with/without T3 and HCC specimens. The profiling results were validated using qRT-PCR. The overall survival and recurrence-free survival were analyzed using Kaplan-Meier method and further confirmed by online available datasets. Results: In the current study, long non-coding RNA CGU1 was downregulated by T3/TR in vitro. Notably, α-fetoprotein (AFP) mRNA levels were downregulated by T3/TR through repression of CGU1. Notably, AFP mRNA is strongly positively correlated with CGU1 and unfavorable prognosis in non-hepatitis B/non-hepatitis C HCC (NBNC-HCC) group patients. Conclusions: our data collectively suggest that T3/TR/ CGU1/AFP act as a potential prognostic marker in NBNC-HCC. Citation Format: Kwang-Huei Lin, Yang-Hsiang Lin, Yu-Chin Liu. LncCGU1 and AFP serve as important prognostic marker in non-hepatitis B non-hepatitis C hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1810.