Background: Vitiligo is an acquired depigmentation disorder of the skin, resulting from a loss of functioning epidermal melanocytes. Multiple pathogenetic factors have been proposed, including the neural theory, genetic predisposition and impaired anti-oxidative defense. Cytokines are small immuneregulatory molecules that can generate an inappropriate immune response when imbalanced. IFN-γ is a pleiotropic cytokine that is a key regulator of the immune system. In addition to host defense, IFN-γ also contributes to autoimmune pathology by inducing autoantibodies, activating autologous cytotoxic T cells and inducing target cell apoptosis. It plays an important role to induce depigmentation in vitiligo. Aim: In this study, we aimed to determine whether vitiligo is associated with alterations in serum level of IFN-γ or not and to find out its association with disease course, severity, and duration. Methods: This case control study included 40 patients presented with stable (N=22) and active (N=18) vitiligo (non-segmental and segmental), diagnosed on the basis of typical clinical features, were selected as patient group. Forty age and sex matched apparently healthy individuals were also included representing the control group. Also patients with previous skin cancer or premalignant skin lesions, or taking immunosuppressive drugs as methotrexate and patients with hepatitis viral infection and those on INF therapy were excluded. They were 25 females (62.5%) and 15 males (37.5 %), their ages ranged from 18 to 45 years old (mean of 33.53). The controls were 20 females (50%) and 20 males (50%), their ages ranged from 18 to 46 years old (mean of 32.85). Results: The distribution of vitiligo in patients, 60% was vitiligo vulgaris, 25% were segmental vitiligo and 15% were acro-fascial vitiligo. The results showed no statistical significant difference (p-value > 0.05) between patients and control as regard age, sex and family history and showed statistical significant difference (p-value < 0.001) between patients and control as regard serum concentration of IFN-γ. Results also showed statistical significant (p-value < 0.001) positive (r = 0.63) correlation between IFN-γ levels and VASI score in patients group and statistical significant difference (p-value < 0.001) between IFN-γ levels and duration, clinical types and activity of the disease in patients group. Conclusion: This study proved high serum level of IFN-γ may be risk factor for vitiligo progression suggesting that it could be used as a marker for assessing vitiligo activity and may open the way for further therapeutic approaches for vitiligo. Serum IFN-γ is positively correlated with disease duration and severity, although it does not seem to be influenced by age, sex and family history of the patient.