Purpose: This study evaluated the feasibility and effectiveness of autologous adipose-derived mesenchymal stem cell (ASC) transplantation into the lacrimal gland for treating aqueous-deficient dry eye disease (DED) associated with Sjögren syndrome. Methods: Patients with Sjögren syndrome–related DED underwent autologous adipose tissue harvest via liposuction. ASCs were isolated, cultured, and injected into the lacrimal gland (volume ≤50% of estimated gland volume). Clinical evaluations— including Ocular Surface Disease Index (OSDI), tear osmolarity, tear film breakup time (TBUT), Oxford corneal staining, and Schirmer test I—were conducted at 1-, 4-, 16-, and 24-weeks after injection. Visual quality assessments included contrast sensitivity and higher-order aberrations (HOAs). Results: Six patients (mean age 56.1 ± 7.2 years) completed the study. Mean OSDI scores significantly decreased from 48.6 ± 8.4 to 28 ± 2.1. TBUT improved in both eyes (right, 3.3 ± 1.0 to 5.6 ± 1.2 seconds; left, 3.6 ± 1.0 to 6.1 ± 1.6 seconds). Schirmer test I values increased (right, 4.1 ± 0.7 to 7.8 ± 0.7 mm; left, 4.0 ± 0.6 to 7.6 ± 0.5 mm). Oxford staining scores decreased (right, 1.6 ± 0.5 to 0.67 ± 0.2; left, 1.3 ± 0.5 to 0.67 ± 0.2). Tear osmolarity also improved (right, 311.6 ± 6.1 to 299.1 ± 5.8 mOsm/L; left, 309 ± 7.6 to 298.3 ± 7 mOsm/L). HOAs were reduced in one eye. No significant change in contrast sensitivity or visual acuity was observed. No adverse events were reported. Conclusions Autologous ASC transplantation into the lacrimal gland appears to be a safe and promising therapeutic option for aqueous-deficient DED in Sjögren syndrome, offering significant improvement in both objective measures and patient-reported symptoms over a 6-month period.