The pyrite ores are strategic industrial resources which generally serve as raw material for producing sulfuric acid. However, during the mining and industrial processing activities, associated toxic elements of cadmium (Cd) and lead (Pb) could be released into the surroundings, posing a significant threat to local environment and human health. In this study, the Institute for Reference Materials and Measurement (IRMM) sequential extraction scheme was used to investigate the geochemical fractionation of Cd and Pb in pyrite ores from a mining area located in Yunfu, western Guangdong, China. The results showed that most of Cd and Pb (>90%) were predominantly found in the geochemically mobile fractions, indicating that Cd and Pb were readily bioaccessible thus easily assimilated and accumulated by organisms. FESEM-EDS results showed that the studied pyrite ores were mainly composed of O, S, and Fe, while the XRD characterizations suggested that FeS 2 and SiO 2 were the major minerals. The high-resolution transmission electron microscope and element mapping characterization further confirmed that FeS 2 was the main mineral of pyrite ores which contained relatively enriched toxic heavy metals (e.g., Pb and Cd). The findings highlight that an extremely large amount of geochemically mobile heavy metals can be released into the environmental media during the mining and utilization processes of pyrite ores based on IRMM sequential extraction protocol. Therefore, proper countermeasures against environmental risks of utilizing pyrite ores should be taken to mitigate the impacts on local ecosystem and human health.