Infectious mononucleosis is a common infection with significant morbidity. Whereas some physicians have used corticosteroids to relieve acute upper airway obstruction caused by infectious mononucleosis, the efficacy of steroids in relieving pharyngeal pain is unclear. In this randomized controlled trial, adolescents with infectious mononucleosis were randomized to receive 1 oral dose of dexamethasone or placebo. The corticosteroid group reported less pain at 12 hours than the placebo group, but there were no differences in pain at 24, 48, or 72 hours or at 1 week. The short-term benefits of a single dose of dexamethasone may not be sufficient for lasting pain relief.