Progressive multifocal leukencephalopathy (PML) is a very rare complication of immunosuppressive or cytostatic treatment of rheumatic diseases. We describe a patient with a mixed connective tissue disease (MCTD) existing for more than 15 years, who had polyarthritis, myositis, scleroderma-like symptoms, pulmonary involvement, and psychosis of undetermined origin. After a 12-year low-dose corticosteroid therapy and a 4-year azathioprin therapy a quickly progressive PML developed; symptoms included: difficulty in urinating, bladder, articulation, spastic hemiplegia, eye movement malfunction. The patient died after after a few months. PML is an important consideration in the differential diagnosis when a patient with MCTD develops neurologic symptoms.