With increasingly widespread illicit use of cocaine, a broad spectrum of clinical pathologies related to this form of drug abuse is emerging. The most frequently used route of administration of powdered cocaine is intranasal inhalation that leads to nasal septum perforation. The objective of this work is to describe a case report of a cocaine-induced midline destructive lesion (CIMDL) associated with an autoimmune phenomenon. A 44-year-old had nasal obstruction, purulent rhinorrhea, nasal bleeding, crusting, hyposmia, and nasal pain for about 15 months. The patient was diagnosed with systemic lupus erythematosus 25 years ago but did not have any symptoms of the disease. In addition, there were reports of a smoking history, but the patient denied the use of cocaine or other illicit drugs during the first inquiry. In subsequent queries, however, the patient admitted to using cocaine. Upon physical examination, there was extensive destruction of the nasal septum with crusts. Of the laboratory tests ordered, the hemosedimentation speed was 44 mm, with platelets of 479,000, and the P-ANCA and C-ANCA were negative. A computed tomography of the paranasal sinuses showed only septal perforation without sinus injuries. A biopsy of the nasal mucosa showed a chronic inflammatory process with granulation tissue, but without malignancy. Sixty days later, a urine test showed hematuria with dysmorphic erythrocytes (70%), and the P-ANCA was 1/640. Treatment with prednisone and methotrexate was started, and a decrease in the P-ANCA (1/80) occurred. The importance of this case is a reminder of the difficulty in determining a differential diagnosis with an autoimmune disease. The ANCA serology can complicate. Immunosuppressive therapy is limited in CIMDL.