Abstract Aim To investigate, retrospectively over a 1‐ to 16‐year follow‐up period, the strength and independence of the association of different patient‐, tooth‐ and surgery‐related prognostic variables with the outcome of periradicular surgery. Methodology The study cohort included 171 teeth in 154 subjects. Clinical and radiographic measures along with the follow‐up period were used to determine the healing outcome. For statistical analysis, results were dichotomized into healed/healing versus asymptomatic function/persistent disease cases. The association between candidate prognostic variables and asymptomatic function/persistent disease was analysed individually and adjusted for confounding using a multivariate binary logistic regression model. Results The percentage of success ( healed / healing cases) was found to be 83.6%, whereas the percentage of failure ( asymptomatic function/persistent disease cases) was found to be 16.4%. Whilst univariate analysis revealed a positive association of the presence of preoperative signs/symptoms, unsatisfactory quality of the coronal restoration, pronounced root‐end resection bevel and inadequate quality of root‐end filling with asymptomatic function/persistent disease , after multivariate binary logistic regression analysis only the unsatisfactory quality of the coronal restoration and inadequate quality of root‐end filling were strongly and independently associated with disease status. Confounding and interaction effects between candidate prognostic variables was noted. Conclusions The findings of this study suggest that whilst the quality of both the coronal restoration and the root‐end filling might be the foremost prognostic variables in periradicular surgery, there are synergistic biological interactive and mutually confounding effects with respect to root‐end resection bevel and preoperative signs and/or symptoms that may be also associated with an increased proportion of failures after periradicular surgery.