11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1) is a candidate gene for hypertension, diabetes, and obesity through altered glucocorticoid production. This study explored the association of 11betaHSD1 gene variants with diabetes, hypertension, and obesity in a longitudinal population study of American Indians (N=918; exams=5508). In multivariate mixed models assuming an additive effect of genotype, a 5' upstream variant (rs846910) was associated with blood pressure (diastolic blood pressure beta=1.58 mm Hg per copy of the A allele, P=0.0008; systolic blood pressure beta=2.28 mm Hg per copy of the A allele, P=0.004; mean arterial blood pressure beta=1.83 mm Hg per copy of the A allele, P=0.0006) and hypertension (odds ratio=1.27 per copy of the A allele, P=0.02). However, birth date modified these associations (test for interaction: diastolic blood pressure P=0.16; systolic blood pressure P=0.007; mean arterial blood pressure P=0.01), such that the magnitude and direction of association between genotype and blood pressure changed with time. Finally, in models controlling for potential confounding by population stratification, we observed evidence of within-family effects for blood pressure (diastolic blood pressure beta=1.77 mm Hg per copy of the A allele, P=0.004; systolic blood pressure beta=2.04 mm Hg per copy of the A allele, P=0.07; mean arterial blood pressure beta=1.85 mm Hg per copy of the A allele, P=0.01) and for hypertension (odds ratio=1.26 per copy of the A allele; P=0.08). No association was observed for obesity. Associations with diabetes were similar in magnitude as reported previously but were not statistically significant. These data demonstrate association between genetic variability at 11betaHSD1 with hypertension, but these effects are modified by environmental factors.