Cerebral single-photon emission computed tomography (SPECT) is a sensitive technique for the detection of central nervous system (CNS) involvement in systemic lupus erythematosus (SLE). The objectivewas to determine whether a relationship exists between cerebral hypoperfusionas detected by cerebral SPECT, cumulative tissue damage and the clinical activity of SLE. Cerebral technetium-99m-L, L-ethyl cysteinate dimer (99mTc-ECD) SPECT was performed in two groups of patients: 10 women with SLE (Group A) who had no previous history of major neuropsychiatric(NPS) manifestations and no minor NPS symptoms in the last six months, and 57 unselected women with SLE (Group B). In the same week that SPECT was performed, the SLE disease activity index (SLEDAI), SLICC/ACR damage index, native anti-DNA antibodies (ELISA) and erythrocyte sedimentation rate (ESR) were determined. In Group A, cerebral SPECT showed moderate or severe hypoperfusion (abnormal SPECT) in five patients without NPS symptoms, unrelated to age (mean 24.8 versus 27.8 years) or disease duration (mean 6.8 versus 9 years). Patients with significant cerebral hypoperfusionhad greater clinical disease activity (mean SLEDAI 13.6 versus 7.6) (SLEDAI > 7 in 5/5 versus 1/5; Fisher: 0.023; OR: 33; 95% CI: 2.3-469.8) and ESR (mean 43.6 versus 9.8; P < 0.05). In Group B, the mean age of the 57 unselectedwomen with SLE was 37 years (SD 6.3) and the mean duration of the disease was 9.7 years (SD 6.3). Cerebral SPECT revealed normal perfusion or mild hypoperfusion (normal SPECT) in 30 patients (52.6%), and moderate or severe hypoperfusion in 27 (47.4%). Hypoperfusion was unrelated to age, duration of SLE or concentrations of anti-DNA antibodies and C3 and C4 fractions. Patients with significant cerebral hypoperfusion had more active clinical disease (mean SLEDAI 13.92; SD 8.44 versus 4.56; SD 4.15) (Mann-Whitney, P < 0.005), more cumulative tissue damage (mean SLICC 2.66; SD 2.84 versus 1.03; SD 1.51) (Mann-Whitney, P 0.035), and higher ESR values (mean 28.7; SD 22.5 versus 17.7; SD 13.3) (Mann-Whitney, P 0.023) than patients with normal SPECT studies. Significant cerebral hypoperfusion was related both to NPS manifestations present at the time of the study (17 of 27, 63% versus 3 of 30, 10%) (OR: 15.3) and cumulative manifestations (19 of 27, 70.4% versus 8 of 30, 26.7%) (OR: 6.5), whether mild (OR: 5.5) or severe (OR: 8.2). In conclusion, cerebral hypoperfusion detected by SPECT in patients with SLE is related to clinical activity (SLEDAI), cumulative tissue damage (SLICC) and concomitant or previous NPS manifestations.