Silica Nanoparticles (SNPs) have been found to exhibit higher cytotoxicity to various cancer cells than to normal cells, while the underlying mechanisms are not fully understood. Here, SNPs triggered much higher cytotoxicity and apoptosis rate in human hepatoma HepG2 cells than in their normal counterparts L-02 cells; we thus selected these two cell lines as the cell model to investigate the mechanisms involved in the SNP-induced selective toxicity to cancer cells. Although uptake pathways and cellular trafficking of SNPs in HepG2 and L-02 cells were similar, more SNPs were taken up and accumulated in the mitochondria of cancer cells. After the removal of free SNPs from the culture medium, nanoparticles were excreted from HepG2 cells more effectively in the first 24 h, but 72 h later more SNPs still remained in cancer cells, leading to the continuous drop in cell viability of HepG2 cells. SNPs triggered a higher ROS generation, along with a lower intracellular GSH content and CAT activity in HepG2 cells than in L-02 cells. This could be due to the fact that HepG2 cells showed a much lower tolerance to H2O2-induced oxidative stress and cell death. Thus, the selective cytotoxicity of SNPs towards cancer cells could probably be explained by the higher particle uptake efficiency and cell sensitivity to oxidative stress as observed in HepG2 cells. [ABSTRACT FROM AUTHOR]