OBJECTIVE: This report describes 6 cases that demonstrate persistent periapical radiolucent lesions after conventional root canal treatment. STUDY DESIGN: Six teeth that had conventional root canal treatment or re-treatment with nonresolving periapical radiolucencies underwent periapical surgery. Biopsies were obtained and analyzed descriptively by correlative light and transmission electron microscopy for general features and microbial findings. RESULTS: Three findings were identified: periapical lesions with persisting infection in the apical root canal system (2 cases); a cyst (1 case); and periapical healing by scar tissue formation (2 cases). CONCLUSIONS: These results confirm previous observations that associated factors in the failure of endodontic treatment include persistent intraradicular infection and periapical cysts. In addition, unresolved periapical radiolucencies may occasionally be due to healing by scar tissue, which may be mistaken as a sign of failed endodontic treatment.