Apolipoprotein E (APOE) is a glycosylated protein with multiple biological properties. APOE gene polymorphism plays a central role in lipid metabolism and has recently been suggested to regulate inflammation. Our objective is to evaluate whether APOE polymorphism affects susceptibility to SLE. APOE genotyping was performed using ApoE StripAssay (TM) kit. Results indicated significantly higher frequencies of allele epsilon 4 and genotype epsilon 3/epsilon 4 and lower frequencies of allele epsilon 3 and genotype epsilon 3/epsilon 3 in SLE patients than controls. APOE epsilon 2 allele was found in three patients, whereas it was absent in controls. The frequencies of allele epsilon 4 and genotype epsilon 3/epsilon 4 were significantly higher in SLE patients with renal involvement and those of alleles epsilon 2, epsilon 4 and genotypes epsilon 2/epsilon 3, epsilon 3/epsilon 4 were higher in patients with neuropsychiatric symptoms. It is concluded that APOE allele epsilon 4 is associated with susceptibility risk/clinical manifestations of SLE and epsilon 2 may increase its severity while epsilon 3 is protective for SLE in Saudis.