Objective To analyze the efficacy and safety of 308 nm excimer light combined with carbon dioxide fractional laser in the treatment of refractory vitiligo. Methods A total of 60 patients with refractory vitiligo admitted to our hospital from December 2022 to April 2024 were selected as the research objects. They were divided into control group (n =30) and study group (n =30) by random number table method. The control group was treated with 308 nm excimer light, and the study group was treated with 308 nm excimer light combined with carbon dioxide fractional laser. The clinical efficacy, adverse reactions, inflammatory factor levels and white spot area were compared between the two groups. Results The total effective rate of treatment in the study group was 96.67%, which was higher than 76.67% in the control group (P <0.05). There was no significant difference in the incidence of adverse reactions between the two groups (P >0.05). After treatment, the levels of IgG and IL-17 in the two groups were lower than those before treatment, and those in the study group were lower than those in the control group (P <0.05). The white spot area of the two groups after treatment was smaller than that before treatment, and that of the study group was smaller than that of the control group (P <0.05). Conclusion 308 nm excimer light combined with carbon dioxide fractional laser is effective in the treatment of refractory vitiligo, which can effectively inhibit the level of inflammatory factors, reduce the area of white spot, and will not increase the risk of adverse reactions. The application effectiveness and safety are high.