We investigated the role of common β2-adrenergic receptor (ADRB2) rs1042714 (Gln27Glu) and rs1042713 (Arg16Gly) polymorphisms on body weight and body composition response to 12-week energy-restricted diet in women. The study comprised 78 Spanish obese (BMI: 34.0 ± 2.8 kg/m²) women (age: 36.7 ± 7 years). We measured (before and after the dietary intervention) weight and height, and BMI calculated. Moreover, body fat mass and lean mass (LM) were measured by dual energy X-ray absorptiometry. We observed an interaction effect between the Gln27Glu polymorphism and diet-induced changes on body weight (P = 0.006), BMI (P = 0.004), and LM (P = 0.001). Women carrying the Glu allele had a greater reduction in body weight than non-Glu allele carriers (9.5 ± 2.9 vs. 7.0 ± 3.5%, respectively, P = 0.002). Moreover, women with the Glu allele lost more LM than the Gln27Gln group (5.9 ± 2.7 vs. 4.0 ± 2.7%, respectively, P = 0.001). We did not find any significant interaction effect between the Arg16Gly polymorphism and diet-induced changes on the outcome variables (all P > 0.1). The results suggest that the ADRB2 Gln27Glu polymorphism has a modulating effect on diet-induced changes on body weight and body composition, and should be considered in future obesity treatments. These findings should be taken as preliminary and be replicated in further energy restriction studies with larger sample sizes.