Background In the United States, hypertension is a risk factor for many diseases, including heart disease, stroke and kidney disease. Known predictors of hypertension include age, race, heredity, environmental and behavioral factors. African Americans have a higher chance of developing hypertension over a lifetime and at an earlier age than Caucasians. This research analyzed the association of the PDE4D_ polymorphism with blood pressure. Phosphodiesterase enzymes have been show to play a significant role in regulation of inflammation in the body and that there is some association between the increased presence of inflammatory cell mediators and development of hypertension. Previous research has shown this polymorphism to be associated with stroke and carotid atherosclerosis. Methods Data analyzed in this research came from two separate preexisting study populations, the Veterans Affairs Hypertension Primary Care Longitudinal Cohort (VAHC) and the African American Study of Kidney Disease and Hypertension Cohort (AASK). Three datasets were analyzed across these two populations: multiple ethnicity VAHC cohort, VAHC African-American subset and AASK cohort. Multivariate linear regression was performed to assess the association of the PDE4D_1 polymorphism and blood pressure. The Bonferroni Method was used to compare the adjusted mean arterial blood pressure (MAP) averages between genotypes for each dataset. Results In the VAHC cohort (p=0.0811) and VAHC African-American subset (p=0.0583), the polymorphism was only marginally associated with mean blood pressure after controlling for the other variables in the model. A marginal significant difference (p=0.0535) in blood pressure averages was detected between the AA and AT genotypes in the African-American VAHC subset. Analysis of the AASK cohort identified baseline diuretic use as an interaction term with the polymorphism. Therefore the final model was stratified by baseline diuretic use. For patients not taking baseline diuretics, the polymorphism was not significantly associated (p=0.3806) with blood pressure after controlling for the other variables in the model. For patients taking baseline diuretics, the polymorphism was found to be significantly associated (p=0.0260) with blood pressure after controlling for the other variables in the model. A statistically significant difference (p=0.0070) in blood pressure averages was detected between the AT and TT genotypes in the AASK cohort. Discussion This is the first known research exploring the association of the PDE4D_1 polymorphism and blood pressure in both multiple ethnicity and African American hypertensive study populations. Results did not yield conclusive evidence that the PDE4D_1 polymorphism was significantly associated with blood pressure in either the VAHC or the AASK datasets. When comparing both the VAHC African-American subset and the AASK cohort, the results were not consistent. The PDE4D_1 polymorphism was not found to be significantly associated with blood pressure in the VAHC cohort. However, there was a significant association between the PDE4D_1 polymorphism and blood pressure in patients taking baseline diuretics in the AASK cohort. Genetic association studies are characteristically limited by the small effect size of the genetic variant. The influence of the PDE4D_1 polymorphism on final gene expression is not yet fully understood. Additional in vitro studies are needed to better understand the mechanisms along the biological pathway from gene expression to enzyme translation that may ultimately affect blood pressure.