ObjectiveAttention-Deficit/Hyperactivity Disorder (ADHD) in adulthood is a complex neuropsychiatric condition characterized by inattention, hyperactivity/impulsivity, often associated with emotional dysregulation, with a significant impact on global functioning, self-esteem, and quality of life. The aim of this study is to compare the effects of atomoxetine and methylphenidate on quality of life and self-esteem in adults diagnosed with ADHD.MethodsA naturalistic observational study was conducted on a sample of adults, divided into methylphenidate and atomoxetine treatment groups. Assessments were performed at baseline (T0) and after a mean period (T1) of 176.37 (± 173.83 SD) days using Barkley Adult ADHD Rating Scale-IV (BAARS-IV) Quick Screen, Adult ADHD Quality of Life (AAQoL-29), Rosenberg Self-Esteem Scale (RSES), and Global Assessment Functioning (GAF).ResultsAt T1, we showed a significant improvement in both groups in all dimensions: reduction of ADHD symptoms (BAARS total: p = 0.012), increase in overall quality of life (AAQoL-29 total: p < 0.001) and global functioning (GAF: p < 0.001), as well as an increase in self-esteem scores (RSES total: p = 0.0002). Methylphenidate proved more effective than atomoxetine in improving both quality of life (total AAQoL-29: p = 0.006) and self-esteem (total RSES: p = 0.031). Correlation analysis showed that symptom severity, assessed with the DIVA 5 test, was inversely proportional to levels of self-esteem (Spearman rho = -0.3269; p = 0.0131) and quality of life (Spearman rho = -0.3758; p = 0.0040) and that RSES and AAQoL-29 scores were positively correlated (Spearman rho = 0.6357; p = 0.0000).ConclusionOur study confirms that pharmacological therapy in adult ADHD not only improves core symptoms but also promotes improvement in self-esteem and personal efficacy, essential components for the recovery of psychological and social well-being.