Without peritreatment antibiotics, infectious flare-ups (about 15% incidence) and serious sequelae follow endodontic treatment of asymptomatic teeth with necrotic pulps and associated periapical lesions. Antibiotics administered after endodontic treatment (4-day regimen) reduce the flare-up incidence to about 2%, but hypersensitivity responses, sensitization, resistant microbes, and drug-taking compliance are potential problems. To ascertain whether a specific prophylactic antibiotic (high-dose, 1-day regimen) would preferentially maintain this low flare-up incidence while overcoming antibiotic-related problems, 315 patients with quiescent pulpal necrosis and an associated periapical lesion were randomly given either penicillin V or erythromycin (base or stearate). Evaluations of flare-up after endodontic treatment were done at 1 day, 1 week, and 2 months. A 2.2% flare-up incidence was found, with no statistically significant differences for penicillin (0.0%), base (2.9%), and stearate (3.8%). No hypersensitivity responses occurred. Gastrointestinal side effects were found primarily with the erythromycins (12.4%). A comparative analysis of the data from our first study (no peritreatment antibiotics) and the pooled data from our last two investigations (including the current trial) showed that peritreatment antibiotic coverage significantly reduced flare-ups and serious sequelae after endodontic treatment (p less than 0.001).