Study Objectives: Decreased upper-airway muscle responsiveness is one of the major phenotypes of obstructive sleep apnea. Use of α1-adrenergic antagonists is correlated with decreased muscle responsiveness in animal studies, but this association has not yet been demonstrated in humans. This study examined whether use of α1-adrenergic antagonists is an independent risk factor for sleep apnea in humans. Methods: Data for this retrospective cohort study were obtained from the National Health Insurance Research Database from Taiwan. Between 2000 and 2012, 25,466 patients with hypertension and 18,930 patients without hypertension were enrolled. These groups were divided into α1-adrenergic antagonist users and nonusers, matched by age, sex, and index year. Individuals were monitored for diagnosis of sleep apnea until 2013. Results: After adjusting for propensity score and potential confounders, including age, geographic location, enrollee category, income, urbanization level, comorbidities, and medication, the adjusted hazard ratios (HRs) for development of sleep apnea with α1-adrenergic antagonist use were 2.38 (95% confidence interval [CI] 1.82-3.10) and 2.82 (95% CI 1.79-4.44) in the hypertension and nonhypertension groups, respectively. Similarly, the adjusted HRs for development of severe sleep apnea with α1-adrenergic antagonist use were 2.74 (95% CI 1.78-4.22) and 4.23 (95% CI 1.57-11.40) in hypertension and nonhypertension patient groups, respectively. The interaction between α1-adrenergic-antagonist user and patients with hypertension was tested using multivariable Cox regression. The results showed that there are positive additive interactions for developing sleep apnea and severe sleep apnea, respectively. Conclusions: Our study suggests that patients with hypertension using α1-adrenergic antagonists have a higher risk of sleep apnea. Routine sleep apnea screening would be beneficial for patients with hypertension who take α1-adrenergic antagonists.