Background: Fluoxetine hydrochloride is one of the most commonly used antidepressants in the selective serotonin reuptake inhibitor class. The aim of work: The study was conducted to detect the effect of chronic fluoxetine treatment on pars distalis and the possible therapeutic effect of adipose-derived mesenchymal stem cells (ADSCs). Material and method: Thirty healthy male adult albino rats were classified into four groups. Control group (Group I) included fifteen rats. Fluoxetine treated (Group II) included five rats that received 24 mg/kg/day of fluoxetine dissolved in 1.0 ml of tap water once a day for 30 days. Fluoxetine group treated with ADSCs (Group III) included five rats that received fluoxetine as group (II) for 30 days, then supplied once by ADSCs at a dose of 1 × 106 cells/ rat in the tail vein suspended in 0.5 ml of phosphate-buffered saline (PBS). Recovery group (Group IV) included five rats that received fluoxetine as the group (II) then received no treatment till the end of the experiment. Samples from pars distalis were processed for light, electron microscopic examination, morphometrical and statistical analyses. Results: In the fluoxetine-treated group, there was a disruption in cellular architecture, size, shape, and staining characteristics of pars distalis cells. The administration of ADSCs significantly improved the microscopic appearance of cells, while the recovery group showed some histological changes similar to the fluoxetine group. Conclusion: Fluoxetine induced various deleterious changes in the pars distalis of albino rats. These changes were almost corrected by the ADSCs treatment.