Delusion of parasitosis is often observed in people who usually take psychoactive drugs. Moreover, it can be present in infectious diseases or tumours of the central nervous system, metabolic disorders, deficiency and states systemic disorders, such as Systemic Lupus Erythematosus (SLE). The neuropsychiatric manifestations in SLE patients are common and constitute one of the criteria for the classification of SLE. Presentation as an acute organic mental syndrome is a clinical emergency and it is usually required the admission in the hospital. We report a case of delusion of parasitosis in a middle age woman diagnosed of SLE several years before and with previous corticosteroid therapy, right temporal arachnoid cyst, chronic Lyme disease and hypothyroidism. We analyse the different role of each pathology and the clinical practice difficulties in the management of these disorders.