The effectiveness of 1-visit root canal treatment (RCT), especially for teeth with large periapical lesions, are still being debated. Although, the use of chlorhexidine (CHX) as a final irrigant have been recommended to provide an optimized approach in 1-visit RCT, there is limited knowledge about the outcome of 1-visit RCT using CHX as the final irrigant. The aim of this randomized clinical trial was to evaluate the healing of mandibular molar teeth with large periapical lesions after RCT that was completed in 1 visit using 2% CHX as a final irrigant, comparing the results with a conventional 2-visit RCT as a control group. This study is a prospective, parallel-designed, and single-blinded randomized clinical trial. One-hundred asymptomatic mandibular molar teeth with large periapical lesions were randomly assigned to 2 groups. All teeth were instrumented with Reciproc files with 2.5% sodium hypochloride (NaOCl) and 5% ethylenediaminetetraacetic acid (EDTA) as irrigants. In the intervention group, half of the teeth were treated in 1 visit, receiving an additional final rinse with 2% CHX before obturation; the other half of the teeth, however, were treated in 2 visits with calcium hydroxide (CH) dressings, in the control group. All root canals were obturated with Reciproc gutta-percha cones and AH Plus root canal sealer. All patients were recalled and investigated clinically and radiographically for 48 months. Periapical healing was evaluated statistically using the Mann-Whitney U test, followed by the Friedman and the Wilcoxon tests (α = 0.05). During the 48-month follow-up process, 86 teeth (44 in 1-visit and 42 in 2-visit group) were examined. There were no significant differences between the 2 groups regarding the radiographic healing rates (1-visit group 91% and 2-visit group 88%) (P > .05). In this study, 1-visit RCT using 2% CHX as final irrigant in asymptomatic mandibular molars with large periapical lesions produced favorable healing results, similar to 2-visit root canal treatment with calcium hydroxide.