MRI and 2D-CSI spectroscopy were performed in eight patients with systemic lupus erythematosus who presented with acute onset of neuropsychiatric lupus (NP-SLE), and in seven normal controls to evaluate for differences in metabolic peaks and metabolic ratios between the two groups. Also, the interval change of the metabolic peaks and their ratios during treatment in the NP-SLE patient group was evaluated. Metabolic peaks for N-acetyl-aspartate (NAA), choline (Cho), creatine (Cr), and lactate/lipids (LL) and their ratios (NAA/Cr, NAA/Cho, Cho/Cr, LL/Cr) were determined at initial presentation and 3 and 6 months later. In the eight lupus patients compared to the seven normal controls, NAA/Cho ratios were lower at presentation (1.05 vs 1.25; p = 0.004) and decreased even further at the three month follow-up (0.92 vs 1.05; p = 0.008). In contrast, both Cho/Cr (1.42 vs 1.26; p = 0.026) and LL/Cr ratios (0.26 vs 0.19; p = 0.002) were higher in the lupus patients at presentation compared to the controls and did not significantly change at three and six months follow-up. The NAA/Cr ratios were lower in the lupus patients compared to the controls at presentation but the difference was not statistically significant. However, the mean NAA/Cr significantly decreased from the initial examination to the three month follow-up (1.42 vs 1.32; p = 0.049) but did not significantly change from the three to the six month follow-up examinations. The NAA/Cr, Cho/Cr, and NAA/Cho ratios varied significantly (p < 0.05, p < 0.05, p < 0.05, respectively) between the 17 different locations measured in the brain in all eight patients and seven controls. Both the NAA/Cr ratios and the Cho/Cr ratios were also significantly lower in the gray matter than in the white matter (p < 0.0001) in both patients and controls, whereas the LL/Cr and NAA/Cho ratios were not significantly different. In conclusion, 2D-CSI MR spectroscopy may be useful in the early detection of metabolic CNS changes in NP-SLE patients with acute onset of new neurological symptoms as well as in the follow-up after treatment to assess presence and changes in metabolic brain injury. However, although there are detectable differences between normal individuals and lupus patients it is currently unclear whether these relate to the acute episode. Future studies are needed comparing NP-SLE patients with active CNS involvement with those inactive disease.