BMI represents an internal metabolic and physiological environment that plays a key role in development of high blood pressure (BP) for many Americans. African–American women have a higher prevalence of high BP and being overweight than men or other ethnic groups. This study examines the genetic–environmental interaction effects of single nucleotide polymorphisms and BMI on BP among African–American women using 1418 African–American women and men from the Genetic Epidemiology Network of Arteriopathy study. A total of 403 tests of single nucleotide polymorphism–BMI interaction were conducted using methods of internal replication, cross-validation, and false discovery rate. One single nucleotide polymorphism (located in the ATP6B1 gene, rs2266917) passed adjustments for multiple testing and had a significant independent main effect (P = 0.0018) on diastolic BP among African–American women. A significant sex-specific interaction effect was found between MMP3_rs679620 and BMI in African–American women (P = 0.0009). MMP3_rs679620 (A–G polymorphism) encodes a Lys-Glu nonsynonymous variant at the 45th amino acid of metallopeptidase 3 and indicates a putative functional modification of metallopeptidase 3. These findings were not identified in African–American men. MMP3_rs679620 appears to have a protective effect on diastolic BP in women with high BMI. Surprisingly, MMP3_rs679620 had the opposite effect on women with low BMI, resulting in higher diastolic BP.