Objective To analyze the clinical effect of halometasone cream assisted 308 nm excimer light combined with CO2 fractional laser in the treatment of patients with refractory vitiligo. Methods A total of 41 patients with refractory vitiligo on the face and neck admitted to our hospital from March 2022 to December 2024 were included, and they were divided into the control group (20 patients) and the observation group (21 patients) by the random number table method. The control group was treated with 308 nm excimer light combined with CO2 fractional laser, and the observation group was combined with halometasone cream on the basis of the treatment plan of the control group. The pigmentation score of vitiligo area, skin lesion area, Vitiligo Area Scoring Index (VASI), treatment effect and adverse reaction rate were compared between the two groups. Results Compared with the control group, the pigmentation score of vitiligo area in the observation group increased after treatment, while the lesion area and the VASI decreased (P <0.05). The total effective rate of treatment in the observation group was 100.00%, which was higher than 75.00% in the control group (P <0.05). However, there was no significant difference in the incidence of adverse reactions between the two groups (P >0.05). Conclusion On the basis of the treatment of 308 nm excimer light combined with CO2 fractional laser, using halometasone cream as assisted therapy has a good effect on patients with refractory vitiligo. It can improve the lesion area of vitiligo and the VASI, and does not increase the incidence of adverse reactions.