Purpose: Studies have shown that many hypertensive patients are not taking diuretics despite being a recommended first-line therapy. Hypertensive patients with the Gly460Trp variant in the alpha-adducin gene may be more likely to benefit from diuretic therapy. The purpose of this study was to evaluate whether screening for the Gly460Trp alpha-adducin gene variant could be a cost effective method of preventing stroke and myocardial infarction. Methods: A Markov decision analytic model was developed for three strategies in a hypothetical cohort of non-diuretic treated hypertensive: 1) testing for the Gly460Trp variant to identify patients for addition of a diuretic, 2) no testing for the variant and no addition of diuretic (usual care), and 3) addition of a diuretic regardless of genotype. We used a lifetime horizon and payer perspective. Cost, utility and clinical data were obtained from the literature. One-way, probabilistic, and scenario sensitivity analyses were conducted to evaluate the uncertainty in the results. Assumptions: 70% of patients who screen positive for the alpha adducin variant will have a diuretic added to their therapy; no patient would be switched from their current antihypertensive medication(s) to a diuretic, but instead a diuretic would be added to their current therapy to bias the results against screening; and the addition of a diuretic to antihypertensive therapy for patients with the wild type alpha-adducin has a neutral effect. Results: The testing strategy increased quality adjusted life years (QALYs) by 0.07 (95% confidence range [CR]: 0.00, 0.17) and saved $1,172 (95% CR: -$289, $2961) compared to usual care. The most influential inputs were the strength of the association between the alpha-adducin gene variant and diuretic effect, the cost of the screening test, and the probability of adding a diuretic to hypertensive medication regimen. The strategy of adding diuretics regardless of genotype resulted in equivalent QALYs and saved $54 (95% CR: -$106, $305) compared to testing. Conclusions: Our results suggest that screening for the alpha-adducin gene variant may be a useful mechanism to identify patients most likely to benefit from diuretic therapy and improve compliance with current treatment guidelines. Additional studies documenting the association between the alpha-adducin gene variant, diuretics, and cardiovascular outcomes, and on patient and provider behaviors in response to genetic test results are needed to strengthen these findings.