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We tested whether the Arg389Gly and Ser49Gly polymorphisms of the β1-adrenergic receptor gene ADRB1 and the T393C polymorphism of the G protein α-subunit gene GNAS1 modulate heart rate (HR) and blood pressure responses during an exercise stress test. The study population comprised 890 participants (563 men and 327 women, mean age 58.1 ± 12.6 yr) of the Finnish Cardiovascular Study. Their HR, systolic (SAP), and diastolic arterial pressures (DAP) at rest, during exercise, and 4 min after the test were measured and analyzed by repeated-measurement ANOVA (RANOVA). Genotypes were detected by TaqMan 5′ nuclease assay. In all subjects, and in men and women separately, the T393C of GNAS1 was the only polymorphism with genotype × time interaction in HR over the three study phases ( P = 0.04, RANOVA). None of the polymorphisms presented genotype × time interaction in SAP or DAP responses ( P > 0.10, RANOVA). In all subjects at rest, the Ser49Gly polymorphism of ADRB1 tended ( P = 0.06, ANOVA) to differentiate HR. Arg389Gly polymorphism of ADRB1 affected maximal SAP during exercise ( P = 0.04, ANOVA) and the change in SAP from rest to maximal ( P = 0.03, ANOVA). Arg389 homozygotes, particularly men, were less likely to have ventricular extrasystoles during the exercise (odds ratio = 0.68, 95% confidence interval = 0.51–0.91, P = 0.009, and odds ratio = 0.60, 95% confidence interval = 0.42–0.86, P = 0.006, respectively) than did Gly389 carriers. In conclusion, polymorphisms examined appear to have modulatory effects on hemodynamics in a clinical exercise test setting. However, the effects in absolute numbers were minor and clinically possibly insignificant.