<p>Pharmacogenetic (PGx) testing to guide antidepressant prescribing is becoming increasingly available. However, its uptake into routine psychiatric practice for young people remains limited due to insufficient youth-specific evidence and uncertainty regarding optimal trial design and outcome selection. This pilot study aimed to evaluate the feasibility of implementing a rigorous triple-blind randomized controlled trial to examine PGx-guided antidepressant treatment compared with treatment-as-usual (TAU) in young Australians with depression. The pharmacoGENEtics in Youth Depression (GENE-YD) study recruited young people aged 16–24 years old with major depressive disorder over 13 months, allocating 1:1 to PGx-Guided treatment or TAU. Depressive symptoms and quality-of-life outcomes were measured using rater-administered measures and self-report questionnaires at Baseline and at 6- and 12-weeks follow-up. Feasibility outcomes included recruitment, adherence, attrition, participant satisfaction, and protocol fidelity. Of 73 individuals screened, 55 were eligible and randomized. Baseline data were collected from 39 participants, with 38 completing assessments through Week 12. Adherence to the study protocol and assessment schedule was high, attrition was low, and participant satisfaction was strong. Clinically meaningful improvements were observed, with the PGx-Guided group showing greater reductions in depressive symptom severity, higher rates of treatment response and remission, and improved quality-of-life outcomes compared with TAU. The GENE-YD Study demonstrated that a triple-blind PGx-guided antidepressant trial is feasible and acceptable in young people with depression, with preliminary indications of clinical benefit. These findings support the inclusion of broader patient-centered outcomes beyond symptom change and will inform methodological refinements for future fully powered youth-specific PGx trials.</p>