Background: Vitiligo is a depigmenting skin condition due to the attenuation of melanin in the affected skin area due to specific melanocyte loss. The pathophysiology of vitiligo has been linked to both mitochondrial malfunction and oxidative stress. Dynamin-related protein 1 (DRP1) is a regulator of mitochondrial fission. Uncoupling Protein 2 (UCP2) is an essential mitochondrial protein that regulates cellular energy metabolism. Objectives: This study aimed to assess the gene expression levels of UCP2 and DRP1 in vitiligo patients and correlate those levels with the activity and severity of the disease. Methods: This case-control study included 40 vitiligo patients and 40 age-healthy controls. Gene expression levels of UCP2 and Drp1 were measured using an enzyme-linked immunosorbent assay. Results: The vitiligo group had significantly higher serum UCP2 and Drp1 gene expression levels (p < 0.001 for each) When compared to the control group. UCP2 gene expression showed a significant negative correlation with VIDA score (p < 0.001). Drp1 gene expression showed significant negative correlations with age and duration of vitiligo (p=0.002, 0.001 respectively) and a positive correlation with VIDA score (p < 0.001). Conclusions: The findings suggest the potential role of dysregulation of Drp1 and UCP2 gene expression in vitiligo. For patients with vitiligo, both markers showed prognostic and diagnostic values.