Background: Donafenib is a novel compound similar to sorafenib that functions as a multikinase inhibitor. This phase 1b trial aimed to assess the safety, pharmacokinetics and efficacy of donafenib in treating Chinese patients with advanced hepatocellular carcinoma. Methods: From July 2014 to April 2015, 27 eligible advanced hepatocellular carcinoma patients were enrolled in the trial. They were randomly divided into 200 mg and 300 mg bid groups and received these oral doses of donafenib until the appearance of intolerance or disease progression. Results: Overall, donafenib was safe and well tolerated in the two groups, and most adverse events were grade 1 or 2. Elevated transaminase (n=19, 70.4 %), hypocalcemia (n=19, 70.4 %), and skin toxicity (n=17, 63.0 %) were the most frequently encountered adverse events. Donafenib exhibited high variability in pharmacokinetic parameters. Areas under the plasma concentration-time curve from 0-12 h increased disproportionally to the dose escalation. The treatment resulted in partial response in two patients and a stable disease status in 17 patients, and the median time to progression was 120 days for both groups. Conclusion: The results from this phase 1b trial indicate a favorable safety profile and notable anticancer efficacy of donafenib for treating advanced hepatocellular carcinoma. Comparable or better safety and efficacy were observed for a lower dosage of donafenib compared with sorafenib in the literature.