on behalf of the SOFIA (SOraFenib Italian Assessment) study group A multicenter randomized controlled trial established sorafenib as a standard of care for patients with advanced hepatocellular carcinoma (HCC). Because the study was prematurely interrupted due to survival benefits in the sorafenib arm, we conducted an observational study to adequately assess risks and benefits of this regimen in field practice. Starting in 2008, all clinically compensated patients with advanced HCC and those with an intermediate HCC who were unfit or failed to respond to ablative therapies were consecutively evaluated in six liver centers in Italy, for tolerability as well as radiologic and survival response to 800-mg/d sorafenib therapy. Treatment was down-dosed or interrupted according to drug label. Two hundred ninety-six patients (88% Child-Pugh A, 75% Barcelona Clinic Liver Cancer [BCLC]-C, and 25% BCLC-B) received sorafenib for 3.8 months (95% CI 3.3-4.4). Two hundred sixty-nine (91%) patients experienced at least one adverse event (AE), whereas 161 (54%) had to reduce dosing. Treatment was interrupted in 103 (44%) for disease progression, in 95 (40%) for an AE, and in 38 (16%) for liver deterioration. The median survival was 10.5 months in the overall cohort, 8.4 months in BCLC-C versus 20.6 months in BCLC-B patients (P < 0.0001), and 21.6 months in the 77 patients treated for >70% of the time with a half dose versus 9.6 months in the 219 patients treated for >70% of the time with a full dose. At month 2 of treatment, the overall radiologic response was 8%. Eastern Cooperative Oncology Group performance status, macrovascular invasion, extrahepatic spread of the tumor, radiologic response at month 2, and sorafenib dosing were independent predictors of shortened survival. Conclusion: Overall, safety, effectiveness, and generalizability of sorafenib therapy in HCC was validated in field practice. The effectiveness of half-dosed sorafenib may have implications for tailored therapy.