Purpose: Oral propranolol has become a promising treatment of capillary hemangiomas (CHs) despite concerns of side effects associated with systemic beta-blockers. The objective of this study was to investigate the distribution of propranolol in periocular tissues and in plasma after topical application of propranolol as compared with intravenous and oral administration of propranolol. Methods: Each rabbit received propranolol as ophthalmic solution (1%) in one eye (1.5 mg dose), intravenous injection (1.5 mg dose), or commercially available propranolol oral solution (5 mg dose). The periocular tissues (e.g., eyelids and extraocular muscles) and blood were collected and assayed for propranolol. Results: After topical instillation of 1.5 mg propranolol, high amounts of propranolol were rapidly delivered to the eyelids and extraocular muscles (4 -32 mg/g at 1 h after dosing). The drug in these tissues was slowly cleared, and significant amounts of the drug ( > 0.4 mg/g) were still present at 24 h after the topical application. After oral administration of a clinically relevant dose of 5 mg propranolol, the drug concentrations in the periocular tissues were relatively low ( < 0.4 mg/g) at 1 h after dosing and generally undetectable at 8 h after dosing. After an intravenous injection of 1.5 mg propranolol, the drug concentrations in the eyelids and extraocular muscles were in the range of 0.2 -1 mg/g at 1 h after dosing. The plasma concentration of the drug after the intravenous injection was significantly higher than that after topical application of the same dose. The higher drug concentrations in the periocular tissues of the treated eyes as compared with untreated eyes suggest direct penetration of the drug into the periocular tissues from the administration site after topical application. Conclusions: Topical administration can provide increased concentrations of propranolol in the periocular tissues and, thus, is superior to systemic administration for the treatment of periocular CH.