Previous studies have shown that environmental exposure to heavy metals has been related to epigenetic changes, such as DNA methylation in receptors involved in pathogenesis of asthma. One of these receptors is beta-2 adrenergic receptor (ADRB2). We conducted this study to examine the association between blood aluminum concentration, blood ADRB2 50 untranslated region (50-UTR) methylation level, and childhood asthma control level. Our results showed a significant positive association between high blood aluminum concentration (odds ratio, 16, 95% confidence interval (CI) [3.57 to 71.76], p < 0.001) and high blood ADRB2 50-UTR methylation level (odds ratio, 4.75, 95% CI [1.39 to 16.2], p ¼ 0.013), and risk of uncontrolled asthma. Multivariable logistic regression revealed that higher blood aluminum concentration was independently associated with increased risk of uncontrolled bronchial asthma (odds ratio, 9.10, 95% CI [2.38 to 34.85], p ¼ 0.0013], after controlling for age, sex, and blood ADRB2 50-UTR methylation level. In addition, blood ADRB2 50- UTR methylation level significantly correlated with whole blood aluminum concentration in asthmatic children (r ¼ 0.480, p < 0.001). We concluded that increasing blood aluminum concentration is an important independent correlate of risk for uncontrolled bronchial asthma as well as increased blood aluminum concentration caused ADRB2 50-UTR hyper-methylation with increasing risk of uncontrolled bronchial asthma. Keywords ADRB2, aluminum, asthma control, bronchial asthma, DNA methylation Introduction Bronchial asthma is a respiratory condition that results from a complex interplay between genetic and environmental factors, which is known to be mediated by epigenetics.1,2 Asthma is among the top 20 childhood chronic illnesses for global ranking of disability-adjusted life years. Worldwide, approximately 334 million people suffer from asthma. Mortality rates from asthma in children range from 0.0 to 0.7 per 100,000. Albeit, these figures may be an underestimation.3,4 Aluminum is the most abundant metal in the earth’s crust, is widely distributed in the environment, and is usually introduced into the human body through ingestion and inhalation. Aluminum is not considered an essential element, and it is recognized as a toxic agent in high concentrations. Most of the body load of aluminum is stored in the bones.5 Sources of aluminum exposure inc