Objective To investigate the safety and efficacy of CO2 fractional laser combined with 5-aminolevulinic acid (ALA)-mediated photodynamic therapy (ALA-PDT) for the treatment of refractory flat wart.Methods The 80 patients with facial flat wart were randomly divided into observation group (40 cases) and control group (40 cases).The observation group was treated with CO2 fractional laser combined with 5-ALA-PDT,and the control group was treated with 5-ALA-PDT only.Those with residual lesions after the first treatment were treated with the second or third times.The interval duration between treatments was 2 weeks.The efficacy and the adverse reaction were evaluated after the 2-week,4-week and 6-month after the last treatment.Results Compared with prior treatment,the facial lesions achieved complete response and improvement.The total effective rate of the observation group were 90.0％ (36/40) and 72.5％ (29/40) for the control group,the difference was statistically significant (P＜0.05).There were 2 cases of pigmentation occurred in observation group and 3 cases in control group.The complications including infection and hypertrophic scar were seldom occurred in the two groups.Conclusions The safety and efficacy of CO2 fractional laser combined with ALA-PDT are better than that with ALA-PDT only in the treatment of refractory flat wart.