Posterior reversible encephalopathy syndrome (PRES) is a syndrome encompassing both clinical and radiological manifestations with white matter vasogenic edema predominantly of the posterior and parietal lobes of the brain. It may accompany several medical conditions including immunosuppressive/cytotoxic drugs. We present a case of cyclophosphamide-induced PRES in a patient treated for acute lupus flare with biopsy-proven lupus nephritis. A 23-year-old African American female presented with non-specific symptoms over a six-month period on a medical background of systemic lupus erythematosus and biopsy-proven focal lupus nephritis class III on hydroxychloroquine, prednisone, and mycophenolate mofetil for which she was non-compliant. She was borderline hypertensive, tachycardic, saturating well on ambient air, and alert and oriented. Laboratory workup revealed electrolyte imbalance, elevated serum urea, creatinine, and B-type natriuretic peptide, low serum complements, and elevated double-stranded DNA (dsDNA) with negative lupus anticoagulant, anti-cardiolipin, and B2 glycoprotein antibody. Chest imaging revealed cardiomegaly with small pericardial effusion, left pleural effusion, and trace atelectasis, with no deep vein thrombosis on Doppler ultrasound. She was admitted to the intensive care unit for lupus flare with severe hyponatremia and was continued on mycophenolate mofetil, hydroxychloroquine, and prednisone 60 mg for induction therapy as well as intravenous fluids. Hyponatremia resolved, and blood pressure was controlled. She became fluid overloaded and anuric, with pulmonary edema and worsening hypoxic respiratory failure not responding to diuretic challenges. Daily hemodialysis was started, and she was intubated. Prednisone was tapered down, mycophenolate was switched to cyclophosphamide/mesna. She became agitated, restless, and confused, with waxing and waning consciousness and hallucinations. She was continued on bi-weekly cyclophosphamide for induction therapy. After the second dose of cyclophosphamide, her mentation worsened. Non-contrast MRI showed extensive bilateral cerebral and cerebella deep white matter high-intensity signals suggestive of PRES, which was new compared to one year prior. Cyclophosphamide was held and her mentation improved. She was successfully extubated and discharged to a rehabilitation center. The exact pathophysiological mechanism of PRES is not known. Endothelial damage and vasogenic edema have been hypothesized as possible mechanisms. Severe anemia, fluid overload, and renal failure are some of the causes of endothelial dysfunction and vasogenic edema with disruption of the blood-brain barrier, which were found in our patient, but repeated dosing of cyclophosphamide worsened her condition. Discontinuation of cyclophosphamide led to a significant improvement and complete reversal of her neurologic symptoms, implying that prompt recognition and management of PRES is vital to prevent permanent damage and even death in these patients.