The purpose of this prospective, randomized, double-blind, placebo-controlled study was to determine the effect of penicillin on postoperative pain and swelling in symptomatic necrotic teeth. Forty-one emergency patients participated and each had a clinical diagnosis of a symptomatic necrotic tooth with associated periapical radiolucency. After endodontic treatment patients randomly received a 7-day oral dose (twenty-eight 500 mg capsules to be taken every 6 h) of either penicillin or a placebo control in a double-blind manner. Patients also received ibuprofen; acetaminophen with codeine (30 mg); and a 7-day diary to record pain, percussion pain, swelling, and number and type of pain medication taken. The majority of patients with symptomatic necrotic teeth had significant postoperative pain and require analgesic medication to manage this pain. The administration of penicillin postoperatively did not significantly (p > 0.05) reduce pain, percussion pain, swelling, or the number of analgesic medications taken for symptomatic necrotic teeth with periapical radiolucencies.