Background: Vitiligo is a chronic progressive depigmented skin disorder, characterized by extensive melanocytes destruction. The explanation for the skin problem remains unknown. Human paraoxonase-1 (PON1) is a hepatic calcium-dependent esterase. PON1 is related to high-density lipoprotein (HDL). Reduction in serum PON1 activity has been recorded to be accompanied by certain pathological conditions under oxidative stress situations. Objective: To evaluate the serum PON1 activity as an indicator of oxidative stress in patients with non-segmental vitiligo (NSV). Patients and Methods: This case-control study included 2 groups, group (A) included 20 patients with NSV and group (B) included 20 age and sex matched healthy controls. The Vitiligo Area Severity Index (VASI) score was used to assess the disease severity. Serum PON1 level was measured using enzyme-linked immunosorbent assay (ELISA). Results: The mean VASI score was 9.86±15.61. The mean PON1 level demonstrated a statistically significant difference between both groups (p=0.002), suggesting that vitiligo cases may be associated with low PON1 levels. PON1 levels showed a significant negative correlation with the severity score measured by the VASI. Only PON1 was found to be a significant predictor of vitiligo severity. Conclusion: Vitiligo cases were associated with a reduction in PON1 level, which emphasizes the underlying theory of disease progression and could emphasize the effect of free radicals and leading oxidative damage in vitiligo. Low PON1 was found to be a significant predictor of a higher VASI score.