Objective To explore the effect of 308 nm excimer light combined with CO2 fractional laser in the treatment of refractory vitiligo. Methods A total of 78 patients with refractory vitiligo admitted to our hospital from April 2022 to September 2023 were selected and divided into reference group and combination group by random sampling method, with 39 patients in each group. The reference group was treated with 308 nm excimer light, and the combined group was treated with 308 nm excimer light combined with CO2 fractional laser. The white spot area, serum anti-tyrosinase antibody level, oxidative stress index, Clinical efficacy of treatment and incidence of adverse reactions were compared between the two groups. Results After treatment, the white spot area of the combined group was less than that of the reference group (P <0.05). After treatment, the levels of serum anti-tyrosinase antibody and propylene glycol in the combined group were lower than those in the reference group, and the level of superoxide dismutase was higher than that in the reference group (P <0.05). The total effective rate of treatment in the combined group was 97.44%, which was higher than 82.05% in the reference group (P<0.05). The incidence of adverse reactions in the combined group was 5.13%, which was lower than 15.36% in the reference group, but the difference was not statistically significant (P >0.05). Conclusion 308 nm excimer light combined with CO2 fractional laser can reduce the white spot area of patients with refractory vitiligo, reduce the level of serum anti-tyrosinase antibody, improve the oxidative stress index, and the treatment safety is high.