MicroRNAs (miRNA) are small endogenously expressed non-coding RNAs that negatively regulate expression of protein-coding genes at the translational level. Accumulating evidence, such as aberrant expression of miRNAs, suggests that they play a role in the development of cancer. They have been identified in various tumor types, demonstrating that different sets of miRNAs are usually deregulated in different cancers. To identify the miRNA signatures specific for Hepatitis C virus (HCV)-associated Hepatocellular carcinoma (HCC), miRNA expression profiling of 32 HCC post-HCV infected, 74 HCV-positive and 12 control individuals was carried out using whole genome expression profiling. Differential expression of two individual miRNAs between control and high risk HCV patients was detected and found to possibly target genes related to HCC development and progression. The sensitivity and specificity of miR-618 for detecting HCC among HCV-positive individuals was found to be 64% and 68%, respectively. Whereas, the sensitivity and specificity of miR-650 were 72% and 58%, respectively. Additionally, the sensitivity and specificity for miR-618/650 in tandem were 58% and 75%, respectively. These predictive values are greatly improved compared to the traditional α-feto protein (AFP) level-based detection method. The proposed HCC miRNA signatures may therefore be of great value for the early diagnosis of HCC, before the onset of disease in HCV-positive patients. The significance of this approach is amplified by the use of urine as a sample source as it offers a non-invasive approach for developing screening methods that can reduce mortality rates.