Common functional polymorphisms in β-adrenergic receptor (βAR) genes have been associated with heart failure (HF) phenotypes and pharmacogenetic interactions with βAR blockers. This study evaluated the association between βAR polymorphisms and carvedilol drug response and prognosis in patients with HF. In this prospective cohort controlled study, 326 volunteers were enrolled [146 HF patients (ejection fraction (EF)<50% by Simpson) and 180 healthy controls]. Drug response was evaluated by echocardiography and outcomes were mortality and hospitalization. DNA was extracted from peripheral blood leukocytes, fragments were amplified by the polymerase reaction and genotyped by restriction fragment length polymorphism (RFLP) for Ser49Gly and Arg389Gly βAR-1 polymorphisms and Gln27Glu and Arg16Gly βAR-2 polymorphisms. The study population was in Hardy‑Weinberg equilibrium. The survival rate was adjusted using the Kaplan-Meier method. HF patients showed the following characteristics: EF 35±9%, 69.9% male, age 59±13 years, 50.7% self-identified as black, 46% had ischemic etiology. The mean follow-up of 23 months showed 18 mortalities and 46 hospitalizations. The genotypes Glu27Glu (24.7 vs. 6.1%, p=0.0004) and Arg16Arg (72.6 vs. 22.8, p<0.0001) of βAR2 polymorphisms and Gly49Gly (33.6 vs. 4.3%, p<0.0001) of the βAR1 polymorphism were higher in HF patients compared with controls. Patients with hospital admission showed a significantly higher Gly389 allelic frequency (54.9 vs. 42.1%, p=0.039), and the trend prevailed among patients who succumbed to the disease (61.1%, p=0.047). Black patients with the Ser49Ser genotype showed a reduced survival compared with the Gly49Gly or Ser49Gly genotypes (p=0.028). There was no association between improved LVEF >20% and βAR polymorphisms. HF patients with β-blocker therapy and the Gly389 allele have reduced event-free survival compared to those carrying the Arg389 allele. Additionally, systolic HF outpatients undergoing β-blocker therapy, self‑identified as black and homozygous for Ser49Ser may have reduced event-free survival, while Glu27Glu, Arg16Arg and Gly49Gly genotypes may be associated with risk for HF.