Objectives: The ophthalmic branch of the trigeminal nerve is one of the most frequently involved sites of postherpetic neuralgia. A single-center randomized controlled study was conducted to evaluate the efficacy of local methylcobalamin injection for subacute ophthalmic herpetic neuralgia (SOHN). Methods: One hundred and five patients with a pain score of 4 or greater were randomized to receive a combination of methylcobalamin and lidocaine via local injection (LM group, n = 35), intramuscular methylcobalamin and local lidocaine injection (IM group, n = 35), and oral methylcobalamin tablet and lidocaine local injection (OM group, n = 35) for 4 weeks. Multilevel mixed modeling was employed to examine treatment responses. Results: Pain scores were reduced in all groups, but this reduction was significantly greater in the LM group (6.7 at baseline vs. 2.8 at endpoint) when compared with systemic administration (IM group 6.8 vs. 4.9, OM group 6.7 vs. 5.1). Clinically relevant reduction of pain (>30%) was seen in 91% of patients in the LM group, a significantly greater proportion than in the systemic groups (66% IM group, 57% OM group). Analgesic use reduced significantly in the LM group (94% at baseline vs. 6% at endpoint) but not in systemic groups (IM group 97% vs. 86%, OM group 94% vs. 80%). Health-related quality of life was higher in the LM group than in the systemic groups. In mixed modelling, increased age was associated with a lower response to methylcobalamin. Conclusions: This study indicates that local injection of methylcobalamin produces significant pain relief from SOHN and is superior to systemic administration. &