Objective To explore therapeutic effect of radiofrequency ablation (RFA) guided by contrast-enhanced ultrasound in patient with advanced primary liver cancer following transcatheter arterial chemoembolization (TACE). Methods The patients with advanced primary liver cancer treated with the TACE firstly from January to December 2014 in this hospital were prospectively collected, then were randomly divided into a conventional ultrasound guided RFA group (control group) and contrast-enhanced ultrasound guided RFA group (study group). The complete ablation rate, liver function, serum alpha-fetoprotein (AFP) level, and 1-, 2-, and 3-year survival rates were observed in the two groups. Results A total of 42 patients with advanced primary liver cancer treated with the TACE were enrolled in this study, there were 21 patients in each group. ① There were no significant differences in the baseline data such as the gender, age, BCLC stage, AFP level, and Child grade of liver function between the two groups (P>0.05). ② All the treatments were completed according to the plan, no serious complications or treatment-related death happened. The complete ablation rate of the study group was significantly higher than that of the control group (χ2=5.717, P=0.017), and the AFP level was significantly lower than that of the control group (t=2.618, P=0.012). There was no significant difference in the Child grade of liver function between the 2 groups (P>0.05). ③ The rate of repeat RFA in the study group was significantly lower than that in the control group (χ2=4.434, P=0.035), and there was no significant difference in the TACE treatment rate between the two groups (χ2=1.659, P=0.197). ④ The survival rate of the study group was significantly better than that of the control group by comparing the survival curves (χ2=3.999, P=0.046). Conclusion Contrast-enhanced ultrasound guided RFA is superior to conventional ultrasound guided RFA in treatment of advanced primary liver cancer following TACE.