Systemic Lupus Erythematosus (SLE) is an autoimmune disease that targets the vascular system, and can result in premature atherosclerotic vascular disease. The causes of SLE and many of the SLE associated problems, such as thrombosis, anitphospholipid syndrome, and atherosclerosis, which are significant public health concerns, are thought to be multifactorial, or caused by interactions of many environmental and genetic factors. Several genes have been proposed and studied in conjunction with these manifestations. This study focuses on one of these genes, apolipoprotein H (APOH gene, beta-2-GPI protein). The effects of several polymorphisms within the coding region in the APOH gene have been studied; however, possible effects of the single nucleotide polymorphisms (SNPs) within the promoter region have not been characterized. In this study, 6 SNPs in the APOH promoter were genotyped in 381 SLE women and 497 healthy women controls. This study aimed to determine the association of these polymorphisms with the occurrence of SLE, with the plasma levels of beta-2-GPI, and with the presence of antiphospholipid antibodies (APA). It was hypothesized that the genetic variation in the promoter region of the APOH gene may affect the risk of SLE and may do so through an effect on plasma beta-2-GPI levels or through its influence on APA. Among whites, the risk of SLE was modestly affected by the -1219 SNP (p = 0.057). While in blacks, the -759 SNP (p = 0.022) and the -700 SNP (p = 0.035) showed association with SLE. The haplotype pattern in whites was associated with SLE risk (p = 0.00015). The -643 SNP showed a modest effect on plasma beta-2-GPI levels in white SLE cases (p = 0.096) and black controls (p = 0.081). Significant differences were seen between antibody negative and all antibody positive groups in whites for the -1284 SNP (p = 0.02) and the -759 SNP (p = 0.046). These results suggest that genetic variation in the APOH promoter may affect SLE risk, beta-2-GPI levels, and the occurrence of antiphospholipid antibodies