A common silent single nucleotide polymorphism (393 T>C) in exon 5 of the guanine nucleotide-binding pro- tein systemsubunit (GNAS) gene associates with hypertension, and altered autonomic nervous system function and re- sponse to � -blockade. We examined the effects of GNAS 393 T>C on the acute post-exercise BP response among 48 Caucasian men (mean ± SEM, 43.7±1.4 yr) with hypertension (145.1±1.5/85.5±1.1 mmHg). Subjects self disclosed a fam- ily history of hypertension. Experiments were non-exercise control and 2 exercise bouts at 40% (LIGHT) and 60% (MODERATE) of peak oxygen uptake. Subjects left the laboratory with an ambulatory BP monitor. Genotypes were de- tected using polymerase chain reaction and restriction enzyme digestion. Repeated measure ANCOVA tested if BP dif- fered over time among experiments and GNAS genotypes (n=37, TT/TC; n=11, CC). Systolic BP increased 8.0+3.6 mmHg less (p 0.05). Most men with the GNAS T 393 allele and a family history of hyperten- sion had lower BP after LIGHT (18/20) vs. non-exercise control; whereas 64% of men with the GNAS CC genotype did not have lower BP after LIGHT (7/11), independent of family history of hypertension (p<0.01). Men with the GNAS T 393 allele, a family history of hypertension, and high BP appear to experience the antihypertensive effects of lower intensity, aerobic exercise more so than men with the GNAS CC genotype.