Although a previous pan-cancer study has reported the expression patterns of ITIHs in various tumors, their analyses have been restricted to limited cancer types. We thus comprehensively analyzed the expression profiles and clinical significances of ITIHs in a broader spectrum of cancers from TCGA. Our results showed that ITIHs were primarily down-regulated in tested cancers. The ITIH members were associated with either survival advantage or disadvantage, depending on the cancer type tested and the genes queried. Importantly, we for the first time demonstrated that ITIH1 had substantially decreased expression in liver hepatocellular carcinoma (LIHC) compared with corresponding normal tissue, and its down-regulation adversely impacted patient outcome. Moreover, ITIH1 expression was consistently declining during the progression of LIHC. Further analysis revealed that ITIH1 may be involved in cellular metabolic processes. Our findings established ITIH1 as a potential diagnostic and prognostic biomarker for LIHC, which awaits future experimental validation.