We report a prospective, randomized, blinded, placebo-controlled, 6-way crossover study of intramuscular versus subcutaneous injection of epinephrine in young men. Peak plasma epinephrine concentrations were significantly higher (P < .01) after epinephrine was injected intramuscularly into the thigh than after epinephrine was injected intramuscularly or subcutaneously into the upper arm. We recommend intramuscular injection of epinephrine into the thigh as the preferred route and site of injection of this life-saving medication in the initial treatment of anaphylaxis.