Aim: To evaluate the safety and efficacy of low-dose doxorubicin and 5FU with best supportive care compared to best supportive care alone for patients with advanced hepatocellular carcinoma. Patients and methods: A total of 60 patients (49 male and 11 females) with advanced hepatocellular carcinoma were enrolled. All patients were randomly divided into two groups. Treatment group: patients receive one day cycle of intravenous doxorubicin 20 mg/m2 and 5FU 500 mg along with best supportive care, the cycle repeated every two weeks continuously until disease progression, unacceptable toxicity or patient refusal. Control group (best supportive care only): Patients received supportive treatment in the form of liver support, tonics, and other symptomatic treatment until death or patient refusal. Results: After a median follow- up of one year, all patients died except three patients still alive. There were 5 patients (16.7%) in treatment group (group A) achieved Partial Response(PR) compared to No Response (NR) in all patients (100%) of control group (group B )(P -value 0.052). the median Progression Free Survival (PFS) was 5 months in group A and 3.5 months in group B, ( P- value 0.018), also, in group A the median Overall Survival (OS) was 8 months compared to 6 months in group B, with one year (OS) rates 9.4% and 3.7% in group A and B respectively (P-value 0.125).there were minimal treatment-related toxicities, and all patients completed treatment without interruption. Conclusion: Low dose doxorubicin with 5FU are well tolerated and shows modest anti- tumor efficacy in patients with advanced hepatocellular carcinoma.