Purpose: This study examined polymorphisms at the loci HLA-DQB1, HLA-DRB1, TNFa microsatellite, and D6S89, all which lie within or telomeric to the major histocompatibility complex (MHC) and the apolipoprotein E (APOE) and THO-1 loci in premenopausal African-American women (AAW) for their association with known coronary heart disease (CHD) risk factors. The sample, drawn from community and military sources, included premenopausal AAW (x̄ age=34.18) who were at low risk (n=117) and high risk (n=173) for CHD. Methods: In this case- (high risk) control (low risk) study, venous blood was used for DNA extraction. Polymorphisms were assessed by using a variety of standard polymerase chain reaction (PCR) methods. Allelic controls were used in all reactions, and two individuals sized and concurred on allele assignment in each analysis. Vertical auto profile (VAPI), glucose challenge tests, measurement of insulin levels, blood pressure, body mass index (BMI), and waist-hip ratio (WHR) assessments were conducted by using standardized procedures. Pearson's correlation coefficients and assessment of allele distributions via relative frequency and frequency variance were conducted in relation to military status, risk group, and risk factors by using exact P values and likelihood ratio chi-squared (Irchi2) statistic. The significance level was set at .05. Results: Of the 237 women (low and high risk), 116 of the women in the sample were in Stage I obesity or heavier. Of 237 women (low and high risk), 85 (36%) of the women in this sample were insulin resistant. The frequency of D6S89 allele 185, D6S89 allele 191, TNFa allele 97, and TNFa allele 103 alleles were higher in the high-risk than the low-risk group; and the D6S89 195 allele was higher in the low-risk group. Elevated systolic blood pressure (SBP) was associated with HLA-DRB1*09 and TNFa 117 alleles. APOE*4, TNFa 109, and DRB1*107 alleles were associated with increased relative risk for elevated total cholesterol to high-density lipoprotein (HDL) ratios. APOE*4 and D6S89 193 alleles were associated with an elevated risk for low-density lipoprotein (LDL) or LDL sub-fraction levels. APOE*2 was associated with a lower relative risk for total cholesterol to HDL ratios. Metabolic syndrome was identified in 26.6% of the sample and was associated with the presence of DRB1*09, DRB1*12, and DRB1*15 alleles. Lp(a) levels were positively associated with risks for HDL, HDL2, HDL3, LDL, and total cholesterol. Lp(a) was negatively associated with risks for very low-density lipoprotein (VLDL), triglyceride, fasting blood sugar (FBS), insulin resistance, SBP, weight, and WHR. Conclusion: The association of APOE, DRB1, D6589 and TNFa alleles with risk of CHD suggest that these are candidate genes or linked to genes for CHD in this cohort of AAW. Our data supported elevated plasma Lp(a) as a potential risk factor in AAW; however, its role is still unclear. The premenopausal AAW in this sample had a higher than expected rate of metabolic syndrome, which was associated with DRB1 alleles.