The natural history of syphilis has been altered by the human immunodeficiency virus (HIV) epidemic. Treatment of patients coinfected with syphilis and HIV is currently controversial; progression and relapse of neurosyphilis have been reported. This case report documents failure of primary treatment and neurosyphilitic recrudescence. In a 32-year-old HIV-positive woman with syphilis who had no additional sexual contacts, the disease progressed to neurosyphilis despite three intramuscular doses of penicillin. After extended intravenous penicillin treatment, neurosyphilis later recurred and re-treatment was necessary. Because many urban centers are affected by high rates of sexually transmitted diseases, including common coinfections of syphilis and HIV, further efforts should be made to identify subsets of patients who may be at high risk of syphilitic recrudescence.