Objective:To investigate the clinical efficacy and safety of 90Sr- 90Y β-ray low dose applicator, topical timolol maleate, and their combination in the treatment of superficial infantile hemangioma (IH). Methods:From May 14, 2013 to April 11, 2017, 400 children (126 males, 274 females, age 5.3(3.9, 7.1) months) with superficial IH in Department of Nuclear Medicine, the First People′s Hospital of Foshan were prospectively enrolled. All patients were randomly divided into 4 treatment groups according to the proportion of 1∶1∶1∶1 by the method of random number table: topical timolol maleate (group A, control group), 90Sr- 90Y β-ray low dose applicator (group B), single course applicator combined with timolol (group C), and multi-course applicator combined with timolol (group D). Lesions were followed up to the 104 th week (W104). Cure rate of W104 was considered as primary end point. Efficacy and safety of different treatment were compared. Kruskal-Wallis rank sum test, Mann-Whitney U test, and logistic regression analysis were used for statistical analysis. Results:Totally, 438 lesions in 400 cases were included in this prospective study. There was no significant difference in baseline characteristics among 4 groups ( χ2 values: 1.709-11.616, H values: 3.681-7.653, all P>0.05). As of W104, 11 lesions (2.51%, 11/438) were lost follow-up, 32 lesions (7.31%, 32/438) were with early withdrawal, 357 lesions (81.51%, 357/438) were cured, 15 lesions (3.42%, 15/438) were with residual, 23 lesions (5.25%, 23/438) were with rebound growth, and no serious adverse events occurred in the 4 groups. Multivariate analysis showed that lesions thickness (<3 mm vs ≥ 3 mm, odd ratio ( OR)=16.689, 95% CI: 7.908-35.223; χ2=54.555, P<0.001) and treatment (considering group A as reference category, OR (95% CI) of group B, C and D were 16.842(6.179-45.901), 4.801(2.167-10.638) and 39.127(10.468-146.243), respectively; χ2=47.663, P<0.001) were independent factors affecting the cure rate of W104. 90Sr- 90Y low-dose fractionation radiotherapy was significantly better than topical timolol maleate ( OR=16.842, 95% CI: 6.179-45.901), and the combination with timolol could significantly reduce the cumulative absorbed dose of radiotherapy (group D vs B: 16(8, 16) vs 16(16, 24) Gy; z=-4.947, P<0.001). Conclusion:90Sr- 90Y low dose applicator therapy is superior to topical timolol maleate for superficial IH, and the combination with timolol could significantly reduce the cumulative absorbed dose of applicator.