Recurrent aphthous stomatitis (RAS) is one of the most common diseases of oral mucosa characterized by recurrent painful ulcers. Although many factors have been implicated in its etiology, they are not fully identified. To investigate the involvement of heavy metals accumulated in saliva in the etiopathogenesis of RAS. This is a prospective, comparative, and controlled clinical study investigating the relationship between heavy metal exposure and RAS. The study consisted of 75 patients with idiopathic RAS who presented to our clinic with recurrent oral wound complaints and 74 healthy volunteers. All subjects were interviewed regarding age, acute or chronic diseases, dietary habits, and possible chemical exposure. Lead (Pb), cadmium (Cd), mercury (Hg), copper (Cu), and manganese (Mn) was measured in saliva by inductively coupled plasma-mass spectrometer (ICP-MS). Significance was considered at p < 0.05. Salivary levels of Pb (15.2 +/- 1.1 vs. 7.6 +/- 9.9 mu g/l; p < 0.003), Hg (0.50 +/- 0.60 vs. 0.13 +/- 0.30 mu g/l; p < 0.001; p < 0.001), Cd (0.11 +/- 0.14 vs. 0.06 +/- 0.13 mu g/l; p < 0.021), and Cu (34.9 +/- 22.5 vs. 21.6 +/- 21.9 mu g/l; p < 0.001) were significantly higher in the patient group than that in the control group. There was no significant difference between Mn levels (57.9 +/- 41.6 mu g/l). Higher heavy metal content of saliva in the patients with RAS may induce apoptosis and ulcer in oral mucosa cells through triggering release of reactive oxygen species resulting from oxidative stress resulting DNA damage.