Systemic lupus erythematosus (SLE) is mainly a disease of young women. The problem of coexistent human immunodeficiency virus (HIV) infection is a growing problem in sub-Saharan Africa. We describe a case of active life-threatening neuropsychiatric lupus in a patient with underlying HIV infection. The challenges of interpreting physical signs and laboratory features that are common to both conditions, and the dilemma of treating active SLE with cytotoxics in the immunocompromised patient, are discussed.