OBJECTIVE To compare fluid attenuated inversion recovery (FLAIR) imaging with proton density/T2 weighted (PD/T2) imaging in neuropsychiatric systemic lupus erythematosus (NPSLE). Magnetic resonance imaging (MRI) is commonly used to evaluate NPSLE. However, the specific role of FLAIR versus conventional PD/T2 methods in NPSLE remains uncertain. METHODS We studied 28 patients with NPSLE classified using the 1999 American College of Rheumatology Case Definitions for NPSLE. NPSLE disease activity and brain injury were estimated with the neurologic components of SLEDAI and SLICC, respectively. Axial T1, PD/T2, and FLAIR MR images were obtained at 1.5 Tesla. Lesions visible on PD/T2 and FLAIR imaging were quantitated, classified, and the lesion conspicuity was determined. Statistical comparisons were then made between imaging techniques. RESULTS FLAIR detected significantly more lesions than PD/T2 (p < 0.001), resulting in a 5% greater diagnostic sensitivity, but infarct, leukoencephalopathy, and normal from abnormal were similar between the 2 methods (p > 0.7). Numbers of lesions by FLAIR correlated closely with lesions by PD/T2 (r2 = 0.97, p < 0.0001). Conspicuity of individual lesions by FLAIR was greater than by PD/T2 in cortical, subcortical, and periventricular locations (p < 0.01). Both FLAIR and PD/T2 observations were similarly associated with NPSLE activity and NPSLE brain injury (p < 0.02). CONCLUSIONS FLAIR is more sensitive and demonstrates greater lesional conspicuity than conventional PD/T2 in NPSLE. Lesions on FLAIR are more obvious and less likely to be confused with nonlesional structures, thus FLAIR images have obvious advantages for both clinical care and didactic rounds. FLAIR is a reasonable addition to a NPSLE MRI examination, and will increase diagnostic sensitivity by about 5%.