This study addresses the need for mechanism-based understanding of cognitive impairment in systemic lupus erythematosus (SLE). Using dynamic contrast-enhanced MRI we identified extensive blood-brain barrier (BBB) leakage in 16 of 46 SLE patients. Extensive BBB leakage was associated with worse overall cognitive performance, affecting primarily information processing speed and executive abilities. Our study provides the first compelling evidence for BBB damage in SLE, and links BBB leakage to cognitive dysfunction. These findings highlight the diagnostic potential of BBB imaging and call for research into BBB-targeting therapies.