The aim of the current study was to detect effect of PUVA on JAK/STAT pathway and its relationship with the pathogenesis of Vitiligo. It was a Case-Control study conducted from Abril 2019 to December 2019 in the Dermatology outpatient clinic at Beni-Suef Univeristy Hospital and included 30 patients that had Vitiligo disease (7 males and 23 females), their age ranged from 20 to 50 years, the average age was 33.73±8.7. And 30 age and sex matched healthy controls. All participants were subjected to full clinical and laboratory investigations. Skin biopsies had been taken from all studied participants (Vitiligo cases and healthy controls) to study effect of PUVA on JAK/STAT pathway and its relationship with the pathogenesis of Vitiligo. Tissue expression of JAK/STAT was significantly higher in Vitiligo  skin lesions as compared with healthy skin biopsies taken from controls both before and even after exposure to PUVA. Tissue expression of JAK/STAT decreased significantly after exposure to PUVA in Vitiligo skin lesions. Tissue expression of JAK was significantly higher in Vitiligo skin lesions in patients with positive as compared with negative family history. There was a significant linear moderate positive correlation between tissue expression of STAT and patients' age among studied Vitiligo patients. There was a significant linear moderate negative correlation between tissue expression of STAT and duration of last new lesion among studied Vitiligo patients. There was a significant linear moderate positive correlation between tissue expression of STAT and Vitiligo disease activity (VIDA) score among studied Vitiligo patients. JAK and STAT tissue expression showed a significant linear strong positive correlation among studied population. We suggest that JAK/STAT plays an important role in the pathogenesis of the Vitiligo disease. This could also open a new era for treatment of Vitiligo disease by anti-JAK modalities.