Recently, it was reported that the toxicity of copper particles increases with the decrease of the particle size on a mass basis. To understand this phenomenon, inductively coupled plasma mass spectrometry (ICP-MS) techniques and in vitro chemical studies were carried out to explore how they produce toxicity in vivo. The results suggest that when the sizes of particles become small and down to a nanoscale, copper becomes extremely reactive in a simulative intracorporeal environment. The nanosized copper particles consume the hydrogen ions in stomach more quickly than micron ones. These processes further convert the copper nanoparticles into cupric ions whose toxicity is very high in vivo.