The study of genetic polymorphisms involved in antidepressants (AD) response is essential to provide a personalized medicine approach in the field of depression. β-arrestin 2 (ARRB2) is a candidate gene in the pharmacogenetics of AD as it is involved in the signaling cascade downstream of numerous neurotransmitter receptors. We investigated the association between five ARRB2 single nucleotide polymorphisms (SNPs): rs1045280, rs2036657, rs4790694, rs3786047 and rs452246, and response to AD treatment in a sample of 569 patients with a major depressive episode treated for 6 months. We show that GG/GT patients for rs4522461 (n = 534) and AA/AC patients for rs4790694 (n = 244) have a lower response to AD than other genotype groups (HDRS score of 10.9 vs 8.0 after 6 months, multivariate analysis: p = 0.03; 12.2 vs 9.6, p = 0.02, respectively). These data provide additional evidence that β-arrestin 2 is a regulator of intracellular signal transduction processes involved in AD treatment.