This study aims to determine the prevalence of and variation in cognitive deficits in systemic lupus erythematosus (SLE) patients with a prior history of central nervous system involvement (+Hx CNS), and without (-Hx CNS); and the relationship of SLE-related cognitive deficits to medication dosage and disease activity. Ninety-four participants, 62 SLE and 32 controls, were screened for anxiety and depression before being tested for cognitive functioning. Subjects scoring >17 on the Hamilton anxiety score (HAM-A) and >10 on the Hamilton depressive score (HAM-D) were excluded from the study. After screening, 30 SLE patients, +Hx CNS (n = 11) and -Hx CNS (n = 19), and 22 healthy control subjects remained in the study. Cognitive impairment was identified in 9 (30.0%) SLE patients [5 (45.5%) SLE +Hx CNS patients and in 4 (21.1%) SLE -Hx CNS patients] compared with 0 (0%) control subjects (p = 0.003). The SLE +Hx CNS patients had a higher degree of cognitive impairment than SLE -Hx CNS patients in the area of attention/calculation, auditory comprehension, visuospatial ability, and executive function. Cognitive scores significantly correlated with total disease activity at the onset of SLE (p = 0.005, r = -0.500). Further evaluation of both disease activity and cognitive function in SLE patients is needed to better anticipate and provide for the social care needs of these patients in the activities of daily living.