Oxaliplatin-based chemotherapy is widely used to treat advanced hepatocellular carcinoma (HCC), but many patients develop drug resistance that leads to tumor recurrence. Cancer stem cells (CSCs) are known to contribute to chemoresistance, the underlying mechanism, however, remains largely unknown. In this study, we discovered a specificity protein 1 (SP1)-induced long noncoding RNA--DPPA2 upstream binding RNA (DUBR) and its high expression in HCC tissues and liver CSCs. DUBR was associated with HCC progression and poor chemotherapy response.