The clinical features of neuropsychiatric systemic lupus erythematosus (NPSLE) are heterogeneous. Furthermore, therapeutic decision-making for NPSLE depends on the recognition of clinical syndromes that have not been sufficiently studied. This report describes the case of a 36-year-old woman with NPSLE who exhibited severe cognitive dysfunction and affective psychosis with persistent nihilistic delusions such as those described in the Cotard delusion. The patient insisted for several months that she was already dead. CSF analysis showed elevated levels of anti-ribosomal P antibodies and a positive determination of oligoclonal bands. Additionally, 18F-FDG PET/CT imaging revealed severe bilateral frontal hypermetabolism suggestive of brain inflammation and occipital hypometabolism. Results from the Systematic Lupus Erythematosus Disease Activity Index 2000 and the Systemic Lupus Erythematosus Disease Activity Score were consistent with an active state of the immunological disease. We then determined by an algorithm that this neuropsychiatric event could be attributed to the activity of the underlying immunological disease. Despite immunosuppressive and symptomatic treatment, only a partial improvement in cognition was achieved. The psychopathological features of the Cotard delusion remained unchanged 4 months after onset. However, we observed rapid remission of affective psychosis and significant improvement in cognition following electroconvulsive therapy. Subsequent follow-up examinations showed a sustained remission. This case describes a protracted form of the Cotard delusion, the diagnostic challenges that arise in the context of SLE, and treatment dilemmas that necessitate collaboration between neurology, psychiatry, and rheumatology.