The therapeutic potential of membrane complement regulatory protein (mCRP)-neutralizing antibodies is unsatisfactory, which perhaps lies in the complex role of mCRPs in tumor occurrence and development. As a member of the mCRPs, CD46 is a transmembrane protein with a cytoplasmic domain and is implicated more in the control of the alternative complement pathway than of the classical complement pathway. Growing evidence has revealed that both the CD46 signaling pathway and microRNAs (miRNAs) play an important role in the development and progression of hepatocellular carcinoma (HCC). In the present study, we analyzed mCRP expression in different tumor tissues by employing western blotting and qPCR. To address the potential role of miRNAs in CD46 signaling, we set out to profile miRNA expression in CD46-overexpressed and -silenced HepG2 cell lines. Furthermore, bioinformatic analysis was performed to identify downstream targets of CD46 signaling. We found that the levels of CD46 expression in HCC tissues were significantly higher compared to that in the adjacent normal tissues. After complement-related gene expression profiling and unsupervised hierarchical clustering analysis of 10 HCC tissues, a total of 37 miRNAs showed significantly different expression levels before and after CD46 expression change. By bioinformatic analysis, we identified let-7b and miR-17 as downstream targets of CD46 signaling, and that the expression levels of let-7b and miR-17 were negatively correlated with that of CD46 in HepG2 cells. The present study suggests that CD46 plays an important role in HCC carcinogenesis by regulating let-7b and miR-17.