Background: We investigated whether low skeletal muscle mass (LSMM) defined according to different muscle groups on computed tomography (CT) scans could predict prognosis of advanced hepatocellular carcinoma (HCC). Methods: We analyzed patients who received first-line sorafenib treatment for advanced HCC in a prospective patient cohort between 2007 and 2012. The muscels areas of total skeletal muscle (TSM), paraspinal muscle (PS), psoas muscle (PM), rectus abdominis (RA), and abdominal wall (AW) were evaluated using a single CT slice at the third lumbar vertebra before treatment. LSMM was determined according to the TSM, PS, PM, RA and AW indices, which was calculated as the parameters divided by the square of the body height. Results: We enrolled 137 patients, with a mean age of 57.5 years; 120 were male and 17 were female. Liver disease etiology was hepatitis B virus in 94 (68.6%) patients and hepatitis C virus in 28 (20.4%) patients. All patients had Child–Pugh class A liver reserve. Women had significantly lower TSM index than men did (p< .001). Among men, the optimal cut points of the TSM, PM and RA indices for LSMM diagnosis were 39.1, 8.3 and 2.9 cm²/m², respectively. Patients with LSMM exhibited poorer overall survival than patients without LSMM, whether LSMM was defined by TSM index (median 5.1 vs. 8.0 months, p = 0.007), PM index (median 5.8 vs. 11.8 months, p< 0.001), or RA index (median 7.2 vs. 8.1 months, p = 0.003). After adjusting for clinical variables including underweight, age, tumor extent, and performance status, LSMM defined by TSM index (hazard ratio [HR]: 2.123, 95% confidence interval [CI]: 1.124-4.010, p = 0.020), PM index (HR: 1.855, 95% CI: 1.163-2.959, p = 0.009), or RA index (HR: 1.650, 95% CI: 1.004-2.710, p = 0.048) remained independent predictors for poor OS. Conclusions: LSMM defined by TSM, PM and RA indices are independent predictors for poor prognosis of advanced HCC, even after adjusted for body weight.