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Background α1-Adrenergic receptor antagonists are commonly used to treat benign prostatic hyperplasia. Preclinical studies suggest that they induce cell death and inhibit tumor growth. This study evaluated the risk of prostate cancer death in men using α1-adrenergic receptor antagonists. Methods A population-based cohort study in Stockholm, Sweden (January 1, 2007, to December 31, 2019) included 451 779 men with a prostate-specific antigen test result. Study entry was 1 year after the first prostate-specific antigen test. Men were considered exposed at their second filled prescription. The primary outcome was prostate cancer mortality. Secondary outcomes were all-cause mortality and prostate cancer incidence. Cox proportional hazards regression models were used to calculate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for all outcomes. Inverse-probability weighting with marginal structural models accounted for time-dependent confounders. Results Of 351 297 men in the final cohort, 39 856 (11.3%) were exposed to α1-adrenergic receptor antagonists. Median (interquartile range) follow-up for prostate cancer mortality was 8.9 (5.1-10.9) years; median (interquartile range) exposure time to α1-adrenergic receptor antagonists was 4.4 (2.0-7.6) years. There was no evidence of an association between α1-adrenergic receptor antagonist use and prostate cancer mortality, all-cause mortality, or high-grade prostate cancer. α1-Adrenergic receptor antagonist use was associated with an increased risk of prostate cancer (HR = 1.11, 95% CI = 1.06 to 1.17) and low-grade prostate cancer (HR = 1.22, 95% CI = 1.11 to 1.33). Men whose prostate cancer was treated with α1-adrenergic receptor antagonists underwent more frequent prostate-specific antigen testing. Conclusions Our findings show no significant association between α1-adrenergic receptor adrenoceptor antagonist exposure and prostate cancer mortality or high-grade prostate cancer. Although the preclinical evidence indicates a potential chemopreventive effect, this study's findings do not support it. [ABSTRACT FROM AUTHOR]