Thiazide diuretics (TD) lead to hypokalemia and angiotensin-converting enzyme inhibitors (ACE) and angiotensin receptor blockers (ARB) lead to hyperkalemia more frequently than other antihypertensives. Inter-individual variation in serum potassium on antihypertensive treatments exist and we hypothesized genetic markers may modify the association of treatment class with serum potassium levels. We separately evaluated interactions of SNP-by-TD as well as SNP-by-ACE /ARB on serum potassium levels among users of antihypertensive medication (anti-HTN). Our study included 7 European-ancestry cohorts (EA, N = 1673 TD exposed; N=1262 ACE /ARB exposed; N=1998 reference, users of other anti-HTN) and 4 African-American ancestry cohorts (AA, N = 482 TD exposed; N =411 ACE/ARB exposed; N=1182 users of other anti-HTN). Models were adjusted for age, sex, BMI, potassium supplementation, and ancestry at the cohort level. We filtered results based on an estimated degrees of freedom filter that incorporated SNP imputation quality, minor allele frequency (MAF), and the number of exposed participants. We performed race-stratified fixed effects inverse variance weighted meta-analyses of 2.5 million SNP-by-drug interaction estimates. ACE /ARB data uncovered eleven significant (P<5x10-8, Figure top line) SNPs (smallest P=1.1х10-8; MAF 0.37-0.40) at a single locus among EAs with consistent direction of effect across the 7 cohorts. The SNPs are located between the genes for NR2F1 antisense RNA 1 (NR2F1-AS1) and arrestin domain containing 3 antisense RNA 1 (ARRDC3-AS1) on chromosome 5 (Figure). The ACE /ARB interaction meta-analysis in AAs highlighted a SNP in insulin-like growth factor 1 receptor (IGF1R). The TD interaction analysis did not yield significant results in either race group. In conclusion, genome-wide SNP-by-ACE /ARB interaction analyses for serum potassium uncovered loci that could have future implications for the prevention of arrhythmias due to high potassium levels on a common antihypertensive treatment.