To evaluate the long-term progression of cerebral MRI abnormalities in patients with longstanding SLE, 30 patients (age 53.5 ± 11.3) underwent brain MRI at baseline (b-MRI) and after 19.4 ± 3.7 years of follow-up (fu-MRI). Two neuroradiologists visually analyzed the MRIs comparing: 1) white matter hyperintensities (WMHIs), 2) cerebral volume, and 3) parenchymal defects; these outcomes were also built in a modified MRI scoring system (mMSS) to estimate the cumulative parenchymal damage. The independent risk factors for accrual of MRI brain damage, as well as the association between MRI abnormalities and the development of new neuropsychiatric (NP) manifestations classified according to the 1999 ACR case definition were also analyzed. Twenty-three patients (76.7%) showed worsening of mMSS; 19 (63.3%) had increased number and volume of WMHIs, 8 (26.7%) had significant cerebral volume loss, and 6 (20%) showed new ischemic parenchymal lesions. Only 6 patients had normal MRI. Antimalarial agents (p=0.006; OR 0.08) were protective against worsening of WMHIs. High cumulative dose of corticosteroids (p=0.026; OR 8.8) and dyslipidemia (p=0.044; OR 10.1) were associated with increased mMSS and cerebral volume loss, respectively. Higher mMSS score at baseline was independently associated with worsening of WMHIs (p=0.001; OR 5.7) and development of new NP events (p=0.019; OR 2.0); higher load of deep WMHIs at b-MRI (p=0.018; OR 2.0) was independently associated with stroke risk. This study shows that MRI brain damage in SLE patients progresses independently from NP involvement as effect of potentially modifiable risk factors and it is associated with increased risk of new NP events.