Atmospheric fine particulate matters (PM2.5) can cause adverse health effects through the generation of reactive oxygen species (ROS), which is normally characterized by the oxidative potential (OP). However, the particulate components that are mainly responsible for the ROS-induced OP remain controversial and warrant further investigation, especially in megacities where high exposure exists and particulate composition is complex. In this study, we measured the OP of PM2.5 using the dithiothreitol (DTT) assay with and without chelation of metals in a megacity in southern China, Guangzhou, in January and April. We explored the correlations between OP and various chemical components in PM2.5, including water-soluble ions, organic carbon (OC), elemental carbon (EC), and metal elements. There are strong correlations between OPDTTv (volume-normalized) and concentrations of PM2.5, OC, and EC, while the correlations between OPDTTm (mass-normalized) and mass-normalized water-soluble ions, OC, EC or metal elements are weak. The OP values with chelation were reduced by ~90%, indicating that water-soluble heavy metals were the major contributors to OP of PM2.5 in Guangzhou. On the other hand, correlations between OPDTTm and OC improved significantly after the chelation of heavy metals, implying that OC explains the variance of OPDTTm although its contribution to OP is much smaller than that of heavy metals. We postulate that there might be synergetic effects between water-soluble heavy metals (which contribute most to OP) and OC (which explains the variance of OP) in ROS generation by PM2.5. The findings of the current study provide a better understanding on the critical components in PM2.5 and potential synergism that might be responsible for health effects in urban areas.