The aim of this study was to investigate a relationship between neuropsychiatric SLE (NPSLE), characterized by many different neurological and psychiatric disorders, and the polymorphism of apoE as a neurobiologically important molecule conferring increased risk and a worse prognosis of a variety of CNS diseases. One hundred and forty-six SLE patients and 93 healthy controls were studied. Out of the SLE cohort, 48 patients (32.8%) were diagnosed with NPSLE and further classified according to criteria of onset, extent, relapsing tendency and type of neuropsychiatric impairment. Apolipoprotein E (apoE) polymorphism was determined by PCR-RFLP and confirmed by isoelectrofocusing. The frequency of the epsilon4 allele was significantly higher in the NPSLE group than in the non-NPSLE group (17.7% vs. 3.1%, chi(2)=19.05, p<0.0001). Distribution of apoE genotypes was significantly different between NPSLE and non-NPSLE groups (chi(2)=80.95, p<0.0001). Both epsilon4 allele frequency (17.7% vs 8.6%, chi(2)=5.082, p<0.024) and genotype distribution (chi(2)=7.202, p<0.027) were significantly different between NPSLE group and the controls. The allele epsilon4 was also associated with earlier disease onset (Fisher's test, p<0.036) and peripheral nervous system involvement (chi(2)=8.242, p<0.0041), but not with relapse frequency ( p<0.37) or major/minor subtype of the disease ( p<0.90). The epsilon4 allele carriers did not develop significantly more neuropsychiatric syndromes than non- carriers (1.75+/-0.23 sy (mean +/- SD) in epsilon4 vs 1.85+/-0.19 sy (mean +/- SD) in non-epsilon4 carriers, Mann-Whitney test, p<0.78). In conclusion, the data suggest an association between apoE polymorphism and NPSLE.