Abstract We aimed to compare the efficacy and tolerability of SECOX regimen with sorafenib alone as first-line treatment of advanced HCC in a multicenter, open-label and randomized setting. Patients not suitable for surgery or loco-regional therapies and no prior systemic therapy for advanced HCC were recruited in 3 centres. Eligible patients were randomly assigned to receive either SECOX (sorafenib 400 mg BD continuously, oxaliplatin 85 mg/m2 on D1, and capecitabine 1700 mg/m2 on D1-7 q2w) or sorafenib alone in 1:1 ratio. Primary endpoint was time-to-progression (TTP). Secondary endpoints were tolerability, ORR, OS and PFS. 46 patients (pts) were randomized and treated, of whom 22 were in the SECOX arm. Median age was 64 years and majority were male (72%). 40 pts (87%) were HBV carrier, and 42 pts (91%) had Child-Pugh A liver function. 30 pts (65%) had received prior non-systemic treatment for HCC. Median duration of follow-up was 7.8 months (mos) (range 0.3-25.8). At the time of analysis, 1 pt in the SECOX arm is still receiving treatment. Median TTP was 3.2 mos (95% CI 1.7-5.8) for SECOX vs 2.8 mos (95% CI 1.8-4.0) for sorafenib. The hazard ratio (HR) for TTP was 0.91 (95% CI 0.5-1.7; p = 0.77; predetermined futility boundary HR ≥ 0.86). Median OS was 7.1 mos (95% CI 3.0-15.3) for SECOX vs 12.5 mos (95% CI 7.2-15.4) for sorafenib (p = 0.29). Median PFS was 3.1 mos (95% CI 1.6-5.8) for SECOX vs 2.7 mos (95% CI 1.8-4.0) for sorafenib. 2 pts (9%) and no pts achieved PR in the SECOX and sorafenib arms, respectively. The clinical benefit rate (CR+PR+SD) was 36% for the SECOX arm and 21% for the sorafenib arm (p = 0.50). Incidence of treatment-related AEs (trAEs) was common in both SECOX and sorafenib arms (64% and 71% respectively, p = 0.75). The most common grade 3-4 trAE was ALP increase (14%) for SECOX and hand-foot skin reaction (25%) for sorafenib. Conclusions: The addition of capecitabine and oxaliplatin to sorafenib did not result in significant improvement in TTP.