ABSTRACT Previous pharmacogenetic findings for beta‐blocker pharmacodynamic candidate genes (ADRB1, ADRB2, ADRA2C, GRK4, and GRK5) have been inconsistent. Therefore, the purpose of this study was to determine whether interactions of pharmacodynamic variants with beta‐blocker exposure significantly associated with survival in patients with heart failure with reduced ejection (HFrEF). The 893 patients were 51% self‐reported African American and 49% self‐reported White race, 36% female, and 240 died (27%) over a median follow‐up of 2.8 years. The primary outcome was all‐cause mortality. Using Cox proportional hazards models with time‐varying beta‐blocker exposure and adjusted for clinical risk factors and ancestry, interactions of ADRB1 Arg389Gly, ADRB1 Ser49‐Arg389Gly haplotype, ADRA2C Del322‐325, and GRK4 Ala486Val with beta‐blocker exposure were significant before correction for multiple comparisons (p