The multiple drug intolerance syndrome is a clinical entity characterized by adverse drug reactions to at least three drugs, chemically, pharmacologically and immunogenically unrelated, manifested upon three different occasions, and with negative allergy testing. Symptoms referred by the patients are often subjective, of neurovegetative origin. The aim of the study is to characterize patients suffering from the multiple drug intolerance syndrome from a psychological point of view, and to compare them to healthy subjects. We studied 30 women suffering from the multiple drug intolerance syndrome. All subjects underwent the following psychodiagnostic tests: (1) the State Trait Anxiety Inventory-Form Y, (2) the Zung Self-rating Anxiety Scale, (3) the Zung Self-rating Depression Scale, (4) the Quality of life enjoyment and satisfaction questionnaire, (5) the Minnesota Multiphasic Inventory-2, (6) the Toronto Alexithymia Scale. The study group was compared to 30 healthy women. When compared with the control group, our patients showed: a higher anxiety, a higher grade of depression, this difference was statistically significant (p < 0.01); a high difference (p < 0.01) between the two groups as regards somatic symptoms; a higher grade of alexithymia (p < 0.01); and a worse quality of life, in all the analyzed ambits. These findings clearly demonstrate the importance of psychological symptoms in patients with the multiple drug intolerance syndrome, and show that a complex allergy and psychological work-up is mandatory in the management of these patients.