Today, mercury is a matter of concern for health and environmental authorities across western countries, and legislation has been passed and programs have been implemented for its total elimination from human activity. But this was not always the case: mercury and its compounds have been highly appreciated and used since remote times all over the world with very diverse purposes ranging from decorative, medicinal, metallurgical and symbolic. In particular, cinnabar (HgS, mercury sulfide), a mineral of an intense red color, has been considered in many cultures as an exotic raw material, highly valued and associated with the elites and sacred practice. In this paper, we examine one such case, set almost 5000 years ago, in Copper Age Iberia, by investigating mercury exposure through human bone. The study presented here includes a total of 170 samples from 70 different human individuals and 22 animals (plus one soil sample) from the Copper Age mega-site of Valencina, south-western Spain. It is the largest ever single-site study of exposure to mercury based on human bone in combination with cinnabar use. Abnormally high values are recorded in some individuals dating between 2900 and 2650 BC, especially in those buried in remarkable tombs belonging to the social elite of this period, but high levels of mercury are also recorded in the rest of the population. Three lines of interpretation are used to explain these results, including the manipulation of cinnabar (grinding it into powder, mixing it with other substances, using it for the decoration of objects, buildings and the human body), its direct consumption through ingestion or inhalation by a ‘special’ social group and the contribution of environmental factors. Based on the currently available evidence, which is carefully reviewed, Valencina represents the most intense and prolonged case of exposure to mercury recorded in human history, which makes it an important site to assess the long and complex history of use of this substance.