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.