: Many patients attribute their health problems to amalgam and other dental metals. In genetically susceptible indviduals, mercury and gold may function as haptens and elicit allergic and autoimmune reactions. The frequency of metal-induced lymphocyte responses was examined in 3,162 patients in three European laboratories using MELISA(R), an optimized lymphocyte proliferation test. The patients suffered from local and systemic symptoms attributed to dental restorations. The effect of dental metal removal was studied in 111 patients with metal hypersensitivity and symptoms resembling Chronic Fatigue Syndrome (CFS). After consultation with a dentist the patients decided to replace their metal restorations with non-metallic materials. The changes in health and in vitro lymphocyte reactivity were studied by inquiries and follow-up MELISA(R). Lymphocyte reactivity was also analyzed in 116 healthy subjects with no complaints of metal allergy. A significant number of patients had metal-specific lymphocytes in the blood. Nickel was the most common sensitizer, followed by inorganic mercury, gold, phenylmercury, cadmium and palladium. As compared to lymphocyte responses in healthy subjects, the CFS group had significantly increased responses to several metals, especially to inorganic mercury, phenylmercury and gold. Following dental metal removal, 83 patients (76%) reported long-term health improvement. Twenty-four patients (22%) reported unchanged health and two (2%) reported worsening of symptoms. Following dental metal replacement, the lymphocyte reactivity to metals decreased as well. We propose that an inflammatory process induced by metals may modulate the hypothalamic-pituitary-adrenal axis (HPA axis) and trigger multiple non-specific symptoms characterizing CFS and other chronic conditions like myalgic encephalitis (ME) and multiple chemical sensitivity (MCS).