Objective: To investigate whether topical mucopolysaccharide polysulfate (MPS) cream can reduce the incidence of eczema and skin atrophy in patients with moderate- or low-risk infantile hemangioma after the treatment with topical beta-blockers or 595-nm pulsed dye laser (PDL) , and to analyze factors influencing the occurrence of eczema and skin atrophy. Methods: A total of 722 patients aged 0- 1 years with moderate- or low-risk infantile hemangioma were enrolled from 5 Children′s Hospitals in China. According to the disease condition and therapy acceptability, these patients were divided into 6 groups to be treated with topical beta-blockers and MPS cream (blocker+ MPS group) , topical beta-blockers (blocker group) , 595-nm PDL and topical MPS cream (PDL+ MPS group) , 595-nm PDL (PDL group) , 595-nm PDL combined with topical beta-blockers and MPS cream (PDL+ blocker+ MPS group) , and 595-nm PDL and topical beta-blockers (PDL+ blocker group) , respectively. All the externally applied agents were applied twice a day, and PDL was performed once every 4 weeks. Efficacy and adverse reactions were evaluated after 3-month treatment. Univariate and multivariate Logistic regression analyses were carried out to analyze factors influencing the incidence of eczema and skin atrophy in patients with infantile hemangioma after treatment, and chi-square test was carried out to compare efficacy among the groups. Results: After 3-month treatment, multivariate Logistic regression analysis for comparing the blocker+ MPS group with blocker group showed that the risk factor for eczema on the surface of hemangiomas was no topical treatment with MPS cream (P= 0.007, OR= 3.887, 95% CI: 1.439-10.493) , while no correlations were observed between the occurrence of skin atrophy on the surface of hemangiomas and analyzed factors. Multivariate Logistic regression analysis for comparing the PDL+MPS group with PDL group showed that no topical treatment with MPS cream (P < 0.001, OR= 7.402, 95% CI: 2.604-21.042) and northern areas (P < 0.001, OR= 67.048, 95% CI: 7.977-563.518) were risk factors for eczema on the surface of hemangiomas, and risk factors for skin atrophy on the surface of hemangiomas included no topical treatment with MPS cream (P = 0.001, OR = 9.371, 95 CI: 2.590 - 33.900) and abundant blood supply of hemangiomas (P = 0.036, OR = 2.971, 95% CI: 1.075-8.208) . Multivariate Logistic regression analysis for comparing the PDL + blocker+ MPS group with PDL+ blocker group showed that risk factors for eczema on the surface of hemangiomas were no topical treatment with MPS cream (P= 0.005, OR= 3.426, 95% CI: 1.446-8.119) and northern areas (P < 0.001, OR= 31.704, 95% CI: 6.924-145.158) , and risk factors for skin atrophy on the surface of hemangiomas included no topical treatment with MPS cream (P < 0.001, OR= 6.011, 95% CI: 2.558-14.126) and southern areas (P= 0.022, OR= 3.021, 95% CI: 1.177-7.753) . After 3-month treatment, the response rate was significantly higher in the PDL group than in the PDL+ MPS group (χ²= 4.531, P= 0.033) , and significantly higher in the blocker group than in the blocker+ MPS group (χ²= 4.344, P= 0.037) . There were no significant differences in the response rate or cure rate among the other groups (all P > 0.05) . Conclusion During the treatment of moderate- or low-risk infantile hemangioma with topical beta-blockers or 595-nm PDL, the combination with topical MPS cream can reduce the occurrence of eczema and skin atrophy without affecting the therapeutic effect.