Background: Hemangioma is one of the most common benign infantile vascular tumors. Corticosteroids were used for a long time for treatment. However, it was associated with many complications. Thus, propranolol was introduced and become the first line of treatment. Initially, it was used orally, and then the topical use gained a wide acceptance. However, no study compared the effectiveness and safety profile of topical when compared to systemic propranolol therapy. Objective: Comparison between systemic and topical propranolol in treatment of infantile hemangioma (IHs). Patients and Methods: The study was carried out at Al-Azhar University Hospitals (Pediatric Surgery Unit) during the period from May 2015 to February 2016. Forty infants with hemangioma were included, and divided into two equal groups: The first group received systemic propranolol therapy; while the second group received topical propranolol therapy. Patients were evaluated before starting the treatment by full history taking and clinical examination. The treatment started in systemic group by 1mg/kg/day divided into three doses; then increased and maintained on 2mg/kg/day till the fifth month, then gradually withdrawn by the end of the sixth month. In topical group, 1mg/kg/day was prepared in an oily base received in daily two divided doses till the end of the sixth month. Outcome was compared between both groups. Results: Topical propranolol therapy was effective as the systemic therapy with low side effects and even better effectiveness. However, the difference was statistically non-significant. In addition, both groups were comparable as regards patient demographics and hemangioma characteristics. Conclusion: Topical propranolol was effective and safe as that or even better than systemic propranolol therapy. However, the small number of the studied subjects prevented the globalization of our results.