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Introduction: The A allele of rs1042713 (Arg16 amino acid) in the β 2 -adrenoreceptor is associated with poor response to long-acting β 2 -agonist (LABA) in young people with asthma. Our aim was to assess whether the prescribing of second-line controller with LABA or a leukotriene receptor antagonist according to Arg16Gly genotype would result in improvements in Pediatric Asthma-Related Quality of Life Questionnaire (PAQLQ)., Methods: We performed a pragmatic randomised controlled trial (RCT) via a primary care clinical research network covering England and Scotland. We enrolled participants aged 12-18 years with asthma taking inhaled corticosteroids. 241 participants (mean±sd age 14.7±1.91 years) were randomised (1:1) to receive personalised care (genotype directed prescribing) or standard guideline care. Following a 4-week run-in participants were followed for 12 months. The primary outcome measure was change in PAQLQ. Asthma control, asthma exacerbation frequency and healthcare utilisation were secondary outcomes., Results: Genotype-directed prescribing resulted in an improvement in PAQLQ compared to standard care (0.16, 95% CI 0.00-0.31; p=0.049), although this improvement was below the pre-determined clinical threshold of 0.25. The AA genotype was associated with a larger improvement in PAQLQ with personalised versus standard care (0.42, 95% CI 0.02-0.81; p=0.041)., Conclusion: This is the first RCT demonstrating that genotype-driven asthma prescribing is associated with a significant improvement in a clinical outcome compared to standard care. Adolescents with the AA homozygous genotype benefited most. The potential role of such β 2 -adrenoceptor genotype directed therapy in younger and more severe childhood asthma warrants further exploration., Competing Interests: Conflict of interest: All authors report study funding from The Henry Smith Charity and Action Medical Research. J. Grigg reports personal fees from AstraZeneca, GSK, Medimmune and BV Pharma, during the conduct of the study. F. Hogarth reports grants from University of Sussex, during the conduct of the study. B. Lipworth reports other (equipment) from GSK, grants, personal fees for advisory board work, consultancy and lectures, and non-financial support for meeting attendance from AstraZeneca, Chiesi and Teva, personal fees for advisory board work from Novartis, grants, personal fees for consultancy and lectures, and non-financial support for meeting attendance from Boehringer Ingelheim, personal fees for consultancy from Dr Reddys, Sandoz, Cipla and Glenmark, during the conduct of the study; personal fees for consultancy from Lupin and Vectura, grants and personal fees for consultancy from Sanofi Regeneron, outside the submitted work; and the author's son is an employee of AstraZeneca., (Copyright ©The authors 2021. For reproduction rights and permissions contact permissions@ersnet.org.)