AIM: Selective intraarterial radionuclide therapy (SIRT) with Yttrium-90 (Y-90) resin microspheres has been applied for hepatocellular carcinoma (HCC) lately. The aim of this study is to present our clinical experience of radiomicrosphere therapy in the treatment of unresectable HCC and determine the proper cases who could benefit from this therapy according to response results yielded by initial staging and control imaging modalities. METHODS: We administered 43 Y-90 microsphere therapy to 34 patients with unresectable HCC (twice in 9 patients). Patients with histopathologically confirmed HCC having a life expectancy of ≥3 months; Child A-B, Okuda stage 1-2 and BCLC stage A-B-C classifications were included in the study. The patients were divided into two groups: Group A consisted of 29 patients who responded to Y-90 therapy (complete response, partial response and stable disease), Group B 5 of non-responders (progressive disease). Predefined parameters were evaluated for response to SIRT and compared between two groups. RESULTS: We found a significant decrease in platelet and lymphocyte counts one month after therapy (p=0.02, p=0.01, respectively). On control imaging tests performed 3 months later, we observed complete response in 19% (n=6), partial response in 44% (n=15), stable disease in 25% (n=8) and progressive diease in 12% (n=5) of the patients. Mean overall survival (OS) was 19 (median value: 14) months. CONCLUSIONS: Y-90 microsphere therapy is a safe and effective treatment option for the patients with unresectable HCC without any serious side effect. Mean tumor dose delivery and lack of bilobar disease seem the best predictors for treatment success.