Small hepatocellular carcinoma is an important leading cause of death amongst cancer patients, our study was designed in order to test the hypothesis that radiofrequency ablation (RFA) combined with a chemotherapeutic drug would improve the outcome for patients. Two groups of patients presenting early small hepatocellular carcinoma were treated with either conventional RFA alone (50 individuals in the control group), or with a combination of RFA and oral sorafenib (40 individuals in an observation group). Individual clinical and laboratory evaluations were done during an average follow-up time of 35 months, and all the data recorded was used to compare results of both treatment approaches. Tumor-free survival, relapse rate and survival rate, RFA interval and number of treatments, overall efficacy and the incidence of complications were analyzed. Serum levels of vascular endothelial growth factor (VEGF), connective tissue growth factor (CTGF), hypoxia inducible factor-1α (HIF-1α) and osteopontin (OPN) were measured and compared. Our results show that the patients in the treatment group had statistically significant prolonged tumor-free survival, decreased relapse and increased survival rates. Also, the patients in the treatment group had significantly more prolonged average intervals of RFA and a lower number of treatments. Furthermore, the overall efficacy in the treatment group was increased, yet the incidence of complications was similar between both groups. Moreover, the serum levels of known tumorigenic factors VEGF, CTGF, HIF-1α and OPN, which were similar between both groups before treatment, improved more markedly after the treatment in the observation group patients. Based on these findings, we propose that sorafenib in combination with percutaneous RFA is safe and efficacious, and a superior treatment for early small hepatocellular carcinoma. Larger studies are needed to corroborate our results.