Sorafenib is an oral anti-angiogenic multi-kinase inhibitor used for systemic therapy in patients with advanced hepatocellular carcinoma (HCC) who are not suitable candidates for surgery or liver transplantation. An earlier study conducted with HCC tumor tissue suggested that ERK phosphorylation (pERK), a downstream target of sorafenib, may serve as a potential biomarker for therapeutic efficacy of sorafenib. However, no study thus far has utilized a minimal invasive procedure to predict HCC patient responsiveness to sorafenib. We evaluated the biomarker utility of circulating endothelial progenitor cells (EPCs) frequency and intracellular pERK levels in EPCs in peripheral blood obtained pre- and post-sorafenib therapy or after transarterial chemoembolistaion (TACE). A statistically significant reduction in the level of ERK phosphorylation and in the absolute number of EPCs was detected following in vivo sorafenib treatment (p < 0 .01 for both). In contrast, the decrease in the level of ERK phosphorylation and EPC number was either marginally significant or insignificant in patients treated with TACE (p = 0.05 and 0.06, respectively). In vitro sorafenib treatment of pre- and post-samples from the same patient cohort inhibited ERK phosphorylation levels in EPCs and decreased the number of EPCs at all doses tested (p = 0.01). Our findings support that the evaluation of both the circulating EPC frequency and the level of ERK phosphorylation in EPCs may serve as potential non-invasive biomarkers of sorafenib efficacy, both as predictor of treatment outcome and efficacy during drug treatment.