Research suggests pulse pressure (PP) is a predictor of cardiovascular disease, and genes likely influence PP levels. Additionally, gender may be an effect modifier between PP and cardiovascular disease. This study addresses whether two renin-angiotensin-aldosterone system (RAAS) variants are associated with PP in a sex-specific manner (genotype-by-sex interaction). Subjects comprised 35,048 GenHAT study participants over 55 years old, approximately half were women and half non-Hispanic white. Blood pressure measurements were obtained 6 months after randomization to one of four antihypertensive medications. The polymorphisms considered were AGT-6 and ACE-I/D. We employed linear regression to assess the interaction. AGT-6 showed a significant (p < 0.001) genotype-by-sex interaction. Men with the 'G/G' genotype had a higher PP (0.6 mm HG) than men carrying an 'A' allele, while 'G/G' women had a lower PP (0.7 mm Hg) than women carrying an 'A' allele. Three of the four treatment groups (chlorthalidone, amlodipine and lisinopril) suggested a consistent interaction in sub-group analyses (only amlodipine was statistically significant, p < 0.001), whereas doxazosin did not. The interaction was evident among non-Hispanic participants but not among Hispanic participants. For ACE-I/D no evidence for a genotype-by-sex interaction was detected. This finding of genotype-by-sex interaction on PP helps our understanding of the complexity of genetic effects on blood pressure.