Abstract: Background and Aims: Sorafenib is the drug of choice in the treatment of advanced hepatocellular carcinoma (HCC). However, its beneficial effect is limited by efficient chemoresistance mechanisms present in tumor cells, which include downregulation and/or impaired function of plasma membrane transporters accounting for intracellular levels of this drug. Thus, decreased expression of the organic cation transporter 1 (OCT1), which plays a major role in sorafenib uptake, has been associated with poorer response of HCC to this drug. Aim: To elucidate whether the presence of OCT1 protein at the plasma membrane rather than the abundance of mRNA/protein of the transporter in tumor cells was related to the treatment outcome. Methods: This is a multicenter retrospective study involving liver tumor biopsy from 39 patients treated with sorafenib for advanced HCC with known outcome (survival, radiological response) of a minimum duration of 4 wk, collected at three German hospitals (TRANSFER study). Endpoint was the relationship between clínico-pathological features and the result of immunohistological examin ation. Immunostaining was performed on whole sections from paraffin-embedded tissue using primary anti-OCT1 antibody. Slides were reviewed independently by two observers blinded to clinical data. Tumors were classified according to a simplified staining score (absent, weak, moderate or strong) and the localization of the staining at the plasma membrane (positive or negative). Results: The results confirmed OCT1 downregulation in approximately half of the cases investigated (10% absent, 39% weak). However, only one third of the tumors expressing OCT1 displayed plasma membrane location of the protein (15% vs. 36% cytosolic expression). When comparing HCC with and without OCT1 expression, no different response to sorafenib was found. However, when tumors expressing OCT1 at the plasma membrane were considered separately, a marked longer survival was found in these patients (Log Rank p < 0.001). No relationship between OCT1 expression at the plasma membrane and (i) stage of the tumor, (ii) previous treatment with TACE or (iii) radiological response was found. Conclusions: These results indicate that the presence at the plasma membrane of tumor cells, rather than the overall OCT1 expression, is related with better outcome of HCC patients treated with sorafenib. Prospective elucidation of the usefulness of OCT1 immunostaining for the guidance of systemic HCC treatment is required

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