Objectives: The aim of the present retrospective cohort study was to assess the 5-year outcome and survival of secondary root canal treatments (2°RCT), exploring the influence of pre-, intra-, and post-operative variables. Materials and methods: One hundred thirty-two endodontically retreated teeth were radiographically and clinically re-examined after 5 years. 2°RCT had been performed during a Masters program following standardized protocols and filled with AH Plus/Thermafil (TF). Pre-, intra-, and post-operative data were collected. The 5-year outcome was blindly evaluated and categorized as healed/diseased on the basis of the periapical index. Bivariate analysis and chi-square test evaluated the association between outcome and 31 demographic/clinical parameters. Multilevel analysis was performed at both patient and tooth level. Statistical significance was calculated at 5% level. Results: At 5-year evaluation, survival rate was 80% with 7.5% lost for endodontic reasons. Eighty-three percent of the teeth were classified as healed. Multilevel analysis identified significant predictors of increased survival: female gender (p = 0.012), absence of a pre-operative metal post (p = 0.017), conservative apical preparation (diameter size < #35) (p = 0.039), teeth restored with a crown (p = 0.009), and final PAI (after 5 years) ≤ 2 (p = 0.001). Multilevel analysis identified as predictor healing: not being a smoker (p = 0.048) and conservative apical preparation < size #35 (p = 0.037). Conclusions: Outcome of 2°RCT filled with Thermafil was successful at 5 years, showing a high rate of survived and healed teeth comparable to that reported previously for other obturation techniques. Clinical relevance: Present findings confirm 2°RCT as a valid therapeutic option to retain natural teeth.