Background: The long noncoding RNA HOTTIP has recently been described as a biomarker of poor prognosis in patients with hepatocellular carcinoma (HCC). Methods: In the present study, we evaluated the clinical significance of HOTTIP expression in predicting the rate of tumor recurrence in HCC patients after liver transplantation (LT). We examined the expression patte and single nucleotide polymorphism (SNP) genotype of HOTTIP in HCC samples from 155 patients underwent LT, and its correlation with clinical parameters and patient prognosis was analyzed. HOTTIP was suppressed using siRNA to explore the role HOTTIP plays in tumor progression. Results: The expression level of HOTTIP in cancer tissues was higher than in adjacent noncancerous tissues. Multivariate analyses revealed that HOTTIP expression was an independent prognostic factor for tumor recurrence and lower overall survival times in HCC patients after LT. Patients who beyond the Milan criteria and exhibit decreased HOTTIP expression experienced longer recurrence-free survival and overall survival. HOTTIP rs2071265 is associated with an earlier recurrence in HCC patients. Moreover, the suppression of HOTTIP in liver cancer cell lines reduced cell invasion rates and increased chemosensitivity. Conclusions: In summary, the high expression level of HOTTIP in HCC could serve as a candidate biomarker for predicting poor prognosis in HCC patients underwent liver transplant therapy. Furthermore, HOTTIP might be a potential therapeutic target.