Abstract—Contributions of the DNA sequence variation at the endothelin 1 locus to the risk of hypertension and to endurance training–induced changes in blood pressure were investigated in the Aerobics Center Longitudinal Study and the Health, Risk Factors, Exercise Training and Genetics Family Study cohorts. We identified 586 normotensive control subjects and 607 incident hypertensive case subjects from the Aerobics Center Longitudinal Study cohort (all whites) who were normotensive and healthy at their first clinic visit. The case subjects were diagnosed with hypertension during an average follow-up of 9.5 years, whereas the control subjects remained normotensive. The allele and genotype frequencies of 5 endothelin 1 haplotype tagging single nucleotide polymorphisms did not differ significantly between the case and control subjects. However, we observed a significant (P=0.0025) interaction between the endothelin 1 rs5370 (G/T; Lys198Asn) genotype and cardiorespiratory fitness level on the risk of hypertension: among low-fit subjects, the rs5370 minor allele (T; 198Asn) was associated with higher risk of hypertension (odds ratio: 1.95; 95% CI: 1.36 to 2.81; P=0.0003), whereas the risk did not differ among genotypes in high-fit subjects. In the white Health, Risk Factors, Exercise Training and Genetics subjects (N=480), the rs5370 T allele was associated with blunted systolic blood pressure (P=0.0046) and pulse pressure (P=0.0016) responses to a 20-week endurance training program. The Lys198Asn variant of the endothelin 1 locus is associated with blood pressure phenotypes in whites. However, the expression of the genotype effect is modulated by physical activity or cardiorespiratory fitness level. Our study provides an illustrative example of how physical activity and fitness level modifies the associations between a candidate gene and outcome phenotype.