To evaluate, by a retrospective cross-sectional case-control study from a single center, the distribution of a number of factors and comorbidities potentially related to central nervous system involvement in SLE Italian patients, a number of "generic" (i.e. not strictly SLE related) and "specific" (i.e. SLE related) risk factors were checked and their distribution analyzed in SLE patients with (NPSLE) and without (SLE) neuropsychiatric (NP) involvement. One hundred and fifty-three SLE patients with NP involvement observed from 1999 to 2008 and 247 SLE patients without NP manifestations, matched for sex, age and disease duration were included in the study. A neuropsychiatric (NP) event represented the heralding symptom of the disease in 40.5% of NPSLE. Headache, cerebrovascular events, mood disorders and seizures were the most frequent NP manifestations. NPSLE patients had a major cumulative number of the investigated factors than controls without NP involvement. Antiphospholipid antibodies (aPL), lupus anticoagulant (LA), Antiphospholipid antibodies syndrome (APS), Raynaud's phenomenon, smoke, assumption of contraceptives and higher cumulative dose of glucocorticosteroids (GC) were significantly more commonly observed among NPSLE. APS and systemic arterial hypertension were more frequently detected among patients with focal NP manifestations, especially cerebrovascular events. aPL, LA, APS, Raynaud's phenomenon, smoke, contraceptives intake and higher cumulative dose of GC did prove more frequently detected in NPSLE patients than in controls. In particular, overall, arterial hypertension should be regarded as a potential independent "risk factor" for focal involvement, especially for cerebrovascular events.