To study the effects of different chemical factors in the gastrointestinal tract, i.e. pH, proteins, amino acids, ionic strength and Na 2 S, on the dissolution of cinnabar. The content of the total mercury in various dissolutions of cinnabar was analyzed by UV/VIS Spectrophotometer. Laser Particle Size Analyzer measured the particle distributions in the dissolution of cinnabar. The chemical species of dissolved substance of cinnabar in the presence of Na 2 S were determined using ESI-MS. The results indicate that the solubility of cinnabar could be increased significantly in the presence of Na 2 S/S 0 , and strong acidic pH, respectively. While the influence of thiol amino acid on promoting dissolution remains relatively low. Cinnabar did not dissolve in the form of nanoparticle. It is postulated that cinnabar could be dissolved in the gastrointestinal tract in various forms of sulfur-containing mercury complexes.Cinnabar is an important constituent of Chinese traditional medicine used as a tranquilizer for more than two thousands years. The molecular mechanism of its pharmacological effects has not been clarified yet. Recently, the toxicity of cinnabar earned increasing attention [1,2]. The active components related to either pharmacological or toxicological action of cinnabar still remain unclear. It is necessary to investigate the potential of the dissolution and absorption mechanism of cinnabar in the gastrointestinal tract.Cinnabar is a naturally occurring mercury sulfide. Its major component is a-mercury sulphide (a-HgS) [3], almost insoluble in water (solubility product lgK sp = −52.03). However, animal experiments suggested that [4,5], oral cinnabar could be absorbed via the gastrointestinal tract, and the amount of mercury absorbed was much greater than theoretical values calculated by the solubility product. Previous research on the dissolution of processed cinnabar showed that cinnabar could dissolve in artificial gastric juice in the form of soluble mercuric salt [6]; however, cinnabar hardly dissolves in artificial intestinal juice. It has also been reported [7] that cinnabar could form complexes with cysteine and glutathione (GSH) and turn into relatively stable coordination complexes in vivo. In addition, environmental chemistry researches revealed that mercury could migrate in the form of mercuric polysulfide complexes extensively in nature [8−10]. The results above provided a new explication for the study on the dissolution of cinnabar.For further research on cinnabar dissolution upon oral administration, it is necessary to compare chemical factors in the gastrointestinal tract to postulate the dissolving forms of cinnabar in vivo. Therefore, we investigated the solubility of cinnabar in different pH, ion strength, amino acids, proteins and sulfide solutions in comparison with that of pure mercury sulphide. The results indicated that dissolved components of cinnabar may include Hg(SH) + , HgS(OH) − , HgS 2 (OH) − , HgS 3 (OH) − in intestinal environment and probably Hg 2 SOH + in gastric environm...