Despite studies concerning toxic reactions related to amalgam components in the literature, few studies have been devoted to evaluate local noxious effects of amalgam tattoos (AT) on biological tissues. In addition, little is known about activation of inflammatory cells by mucosa-implanted amalgam debris. Tissue reaction to AT depends on the particle size. Human leukocyte antigen DR (HLA-DR) is an activation marker of inflammatory cells associated with antigen presentation. Metallothioneins (MT) are proteins involved with metal detoxication, including mercury and silver. The purpose of the present study was to investigate the immunolocalization of HLA-DR and MT in AT with large or powdered particles. Paraffin-embedded AT tissue blocks were sectioned and subjected to immunohistochemistry for HLA-DR and MT localization. The results demonstrated a dense mononuclear inflammatory infiltrate associated with large and powdered debris and positivity for HLA-DR and MT in inflammatory cells. While blood vessel walls and connective fibers impregnated with powdered particles were negative for HLA-DR, they were positive for MT. In addition, wherever epithelial basement membrane impregnation by powdered amalgam particles was observed, a strong positivity for MT was detected. These findings demonstrate that residual elements of AT still have noxious local effects over tissues.