Single-walled carbon nanotubes (SWCNTs) are widely used in industrial and medical sectors, and the increasing exposure of SWCNTs necessitates the studies of their potential environmental and health effects. Considerable efforts have been made to improve the dispersion of SWCNTs by chemical modifications. However, the toxicological effects of such modifications on SWCNTs are mostly unknown. This study was designed to determine the influences of acid functionalization on SWCNT toxicity and to understand the molecular toxic mechanisms. RAW264.7 cells were exposed to 0-50 μg/mL of as-synthesized SWCNTs or acid-functionalized SWCNTs (AF-SWCNTs) for 24 hours and then their toxicities were compared via viability analysis. After that the global gene expression profiles of cells exposed to AF-SWCNTs were obtained and analyzed. The results showed that AF-SWCNTs penetrated cell membrane and aggregated in cell cytoplasm and nuclear areas, resulting in enhanced toxicity. In addition, AF-SWCNTs altered the expression of genes related to ribosome, mitochondria, inflammatory response, cell cycle/apoptosis, and proteasome pathway. The gene expression study excluded the interference of metallic impurities and suggested similar toxic mechanism to that of ultra-fine particulate matters.