Background: To deepen the understanding of the numerous unspecific complaints which are related to the dental material amalgam both in patients and physicians, an interdisciplinary case-control study regarding toxicological, allergic, psychological and psychiatric aspects was conducted. Forty patients with amalgam-associated complaints were compared to a well-matched group of 40 amalgam bearers without complaints. Methods: Patients and controls underwent a dental examination, which included recording of the quantity, surface area and quality of amalgam fillings, a determination of the mercury load in blood and urine, an allergy examination including patch testing with amalgam and a psychometric assessment with questionnaires noting coping strategies (ABI-UMW-P), interpersonal problems (Inventory of Interpersonal Problems) and self-consciousness (SAM), the NEO Five-Factor Inventory, Symptom Checklist-90-R, Beck Depression Inventory and a screening instrument for somatoform disorders. Results: Patients and controls did not differ with respect to mercury concentrations in body fluids. Only 1 patient was found to have a positive amalgam patch test; various other allergies could be determined in 28% of patients (n = 11). Patients had higher levels of psychic distress, a higher incidence of depression and somatization disorders as well as different styles of coping with anxiety compared to controls. Conclusions: No indication for mercury intoxication or amalgam allergy as a cause of the patients’ complaints could be found. The theory of amalgam-related complaints as an expression of underlying psychic problems is supported. Treatment should focus on somatization and changing coping and attribution styles.