 Long non-coding RNAs (lncRNAs) homeobox (Hox) transcript antisense intergenic RNA (HOTAIR) and HOXA transcript at the distal tip (HOTTIP) have been suggested to be implicated in liver cancer tumorigenesis and progression; however, little is known about the role of the plasma HOTAIR and HOTTIP in liver cancer diagnosis and prognosis. The current study aimed at measuring the plasma levels of long non-coding RNAs (HOTAIR and HOTTIP) expression in chronic liver disease (CLD) due to HCV genotype 4 infection with/without cirrhosis and HCC patients in an attempt to evaluate the potential benefits of these new circulating as non-invasive diagnostic biomarkers and a novel therapeutic strategy for liver cirrhosis and carcinogenesis of Egyptian patients. Hundred subjects were included in this study, divided into two groups; group I (50 patients) were classified into subgroup Ia (CLD without cirrhosis, n = 25) and subgroup Ib (CLD with cirrhosis, n = 25), group II (CLD patients with HCC, n = 25), and control (healthy volunteer, n = 25). The expression of lncRNAs (HOTAIR and HOTTIP) genes was analyzed by real-time PCR.