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Sorafenib is the standard treatment of advanced hepatocellular carcinoma. Because of its unique toxicities, improving patients’ tolerance merits close follow-up. Nurses can play a crucial role by leading a patient educational program (EP).The aim of this study was to assess whether adding EP to usual care (UC) improves patient’s care.Since 2011, oncologists referred patients treated by sorafenib to the EP led by clinical nurses. The EP included a visit before the first administration, weekly telephone calls, and a visit with the nurse before each oncologist consultation. We retrospectively compared patients in the EP with those in UC followed by an oncologist and patients included in a clinical trial.Since 2005, 129 patients were treated with sorafenib for hepatocellular carcinoma: 31 in the EP (24%), 22 in a clinical trial (17%), and 76 with UC (59%). Seventy-one percent of the patients in the EP had toxicities identified during a telephone call, which prompted symptomatic measures in 65% of the patients, leading to treatment modification before the planned on-site visit in 29% of the patients. Educational program patients required fewer dose reductions (39% vs 61% for UC, P = .04), and median time to first dose reduction was shorter with EP than with UC (25 vs 45 days, P = .036).This study suggests a clinical benefit of EP related to improved toxicity management of sorafenib that resulted in fewer dose reductions.Patients treated with sorafenib may benefit from an EP. Different types of EP should be compared prospectively, focusing on patients’ quality of life.