Emerging evidence demonstrates that abnormally expressed long noncoding RNAs (lncRNAs) are involved in the progression of various cancers. However, the expression profiles and functions of lncRNAs in hepatocellular carcinoma (HCC) with microvascular invasion (MVI) remain largely unknown. In this study, we revealed the differential expression profiles of lncRNA and messenger RNA in four pairs of HCC with MVI and adjacent nontumor liver tissues by using high-throughput RNA sequencing. Among these dysregulated lncRNAs, lnc-TSPAN12 was the most significantly upregulated lncRNA in HCC. The results of real time-PCR showed that lnc-TSPAN12 was highly expressed in HCC, including HCC with MVI, and its high expression was associated with unfavorable clinicopathological features and poor prognosis. Moreover, multivariate Cox regression analysis verified that lnc-TSPAN12 was an independent prognostic predictor for overall and recurrence-free survival. Receiver operating characteristic curve analysis indicated that lnc-TSPAN12 could serve as a potential diagnostic biomarker for HCC with MVI. In addition, a loss-of-function experiment demonstrated that lnc-TSPAN12 knockdown inhibited HCC cell migration and invasion in vitro. Our findings suggest that lnc-TSPAN12 may function as an oncogene in HCC progression and could serve as a novel diagnostic/prognostic biomarker and potential therapeutic target for HCC with MVI.