22q11.2 deletion syndrome (22q11DS) markedly increases risk of psychiatric disorders, including anxiety and mood disorders, and is associated with a spectrum of cognitive impairment, from borderline functioning to intellectual disability, with cognitive decline frequently reported. Despite widespread use of selective serotonin reuptake inhibitors (SSRIs) in 22q11DS, evidence regarding their safety, effectiveness, and potential effects on cognitive trajectories remains limited. We conducted a retrospective, observational multicenter study across nine international centers, including cross-sectional and longitudinal analyses. In the cross-sectional sample of 190 SSRI-treated individuals with 22q11DS (6-56 years), retrospective data on SSRI type, indication, perceived effectiveness, and side effects were analyzed descriptively (40-190 cases across variables). In the longitudinal analyses, intellectual quotient (IQ) trajectories were compared between 101 SSRI-treated and 213 SSRI-untreated participants (4-34 years) using mixed-model regression analyses. SSRIs were mainly prescribed for mood and/or anxiety disorders (94%) and were rated as overall effective in 71% of cases with available data, with side effects reported in 25%. SSRI-treated participants exhibited stable or modestly increasing IQ trajectories, whereas SSRI-untreated participants showed decreasing trajectories over time. In exploratory analyses, concomitant psychostimulant treatment was associated with the most favorable IQ trajectories. Treatment duration, but not dosage, was positively associated with IQ change. These findings suggest that the effects of SSRI treatment in individuals with 22q11DS may extend beyond symptom management. Controlled prospective studies are needed to confirm these findings and determine underlying mechanisms.