Short‐acting β2‐adrenergic receptor agonists are commonly used bronchodilators for symptom relief in asthmatics. Recent evidence demonstrated that prolonged exposure of cultured airway smooth muscle cells to β2 agonists directly augments procontractile signaling pathways with the change in expression of regulator of G protein signaling 5 (RGS5). The aim of this study was to test whether genetic variants in RGS5 gene affect the response to short acting β2‐agonists. Bronchodilator responsiveness was assessed in 137 asthmatic children by % change in baseline forced expiratory volume in 1 sec (FEV₁) after administration of albuterol. The analyses were performed in patients with FEV₁/FVC ratio below 0.9 (FVC—forced vital capacity, n = 99). FEV₁% change adjusted for baseline FEV₁ values was significantly different between genotypes of rs10917696 C/T polymorphism (P = 0.008). The association remained significant with inclusion of age, sex, atopy, parental smoking, and controller medications into multivariate model (P = 0.005). We also identified additive effect on the treatment outcome with previously published genetic variant G/A rs1544791 in phosphodiesterase 4 (PDE4D) gene. Carriers of two risk alleles (C and G) had adjusted mean % FEV₁ change value 4.6 ± 1.3, while carriers of one and none of the risk alleles had 8.1 ± 0.7% and 13.5 ± 2.4%, respectively, P = 0.001. Our work identifies a new genetic variant in RGS5 demonstrating additive effect with PDE4D, both implicated in modulation of asthma treatment. Pediatr Pulmonol. 2013; 48:970–975. © 2012 Wiley Periodicals, Inc.