Introduction: The aim of this study was to compare the outcome of root canal treatment using either Thermafil (TF; Dentsply Maillefer, Ballaigues, Switzerland) or the cold lateral condensation (CLC) obturation technique in teeth with periapical lesions and to investigate the influence on postoperative pain and treatment outcomes. Methods: After standardized root canal preparation technique, 112 teeth were obturated with either the TF or the CLC technique during 2 sessions by single operator. Postoperative pain, obturation length, and treatment outcomes were recorded. The teeth were reviewed clinically and radiographically for 2 years. Results: Although there were no significant differences between the techniques in the incidence of postoperative pain at 24 hours (P > .05), the incidence of pain was significantly higher in the TF group than in the CLC group at 48 hours (P < .05). During the 2-year follow-up period, there was no statistically significant difference in the success rate of the teeth treated with TF (96.4%) in comparison with those treated with CLC (98.2%) (P > .05). Conclusions: In this study, the outcome of the root canal treatment of teeth using the TF and CLC techniques revealed that these techniques are useful for root canal obturation.