BACKGROUND: Depression is prevalent among older adults, particularly those with somatic comorbidities, and is linked to cognitive decline and reduced quality of life. Driving may act as a protective factor by enhancing cognitive function and social engagement. However, few prospective studies have investigated this association. This study aimed to assess whether driving was associated with a lower risk of new-onset depression and lower antidepressant medication. METHODS: This ancillary study of the prospective S.AGES cohort (Sujets AGÉS-Aged Subjects) which included 3,434 participants (mean age 77.6 ± 6.2 years) with somatic comorbidities (chronic pain, type 2 diabetes, or atrial fibrillation) enrolled between 2009 and 2014. Driving status was recorded at baseline, and participants were monitored for 36 months. Depression was measured by the Geriatric Depression Scale (GDS), and antidepressant prescription was recorded at follow-up. Time-to-event analyses were performed on propensity-matched cohorts comparing drivers and non-drivers for new-onset depression (GDS ≥ 5/15) and antidepressant use. RESULTS: In the first cohort (126 drivers and 126 matched non-drivers), drivers had a significantly lower risk of new-onset depression (hazard ratio [HR] = 0.58 [0.40-0.86]). In the second cohort (368 drivers and 368 non-drivers), drivers had a lower risk of antidepressant use (HR = 0.49 [0.29-0.84]). DISCUSSION: Driving at baseline was associated with a reduced risk of depression and antidepressant prescription in older adults with somatic comorbidities, highlighting the potential importance of maintaining mobility and driving to support mental health in this population. TRIAL REGISTRATION: The study was registered at ClinicalTrials.gov NCT01065909 with a first registration date of February 8, 2010.