Objective: Asthma is the most common chronic disease in children. Short-acting bronchodilator medications are the most commonly prescribed asthma treatment worldwide, regardless of disease severity. Puerto Rican children display the high­est asthma morbidity and mortality of any US population. Alarmingly, Puerto Rican children with asthma display poor broncho­dilator drug response (BDR). Reduced BDR may explain, in part, the increased asthma morbidity and mortality observed in Puerto Rican children with asthma. Gene-environ­ment interactions may explain a portion of the heritability of BDR. We aimed to identify gene-environment interactions as­sociated with BDR in Puerto Rican children with asthma.Setting: Genetic, environmental, and psycho-social data from the Genes-environ­ments and Admixture in Latino Americans (GALA II) case-control study.Participants: Our discovery dataset con­sisted of 658 Puerto Rican children with asthma; our replication dataset consisted of 514 Mexican American children with asthma.Main Outcomes Measures: We assessed the association of pairwise interaction mod­els with BDR using ViSEN (Visualization of Statistical Epistasis Networks).Results: We identified a non-linear interac­tion between Native American genetic ancestry and air pollution significantly as­sociated with BDR in Puerto Rican children with asthma. This interaction was robust to adjustment for age and sex but was not significantly associated with BDR in our replication population.Conclusions: Decreased Native American ancestry coupled with increased air pollu­tion exposure was associated with increased BDR in Puerto Rican children with asthma. Our study acknowledges BDR’s phenotypic complexity, and emphasizes the importance of integrating social, environmental, and bi­ological data to further our understanding of complex disease.Ethn Dis. 2021;31(1):77- 88; doi:10.18865/ed.31.1.77