In the present study, multivariate analyses were performed on clinical and treatment variables that may influence the outcome of endodontic treatment. Data collected in a previous clinical‐radiographic follow‐up study were used. Of 810 treated, 675 roots in 498 teeth were followed for 6 months to 4 yr. Of these, 192 (the CAP group) had pre‐existing, chronic apical periodontitis and 483 (the NAP group) had not. Root canal treatment followed a standard procedure with one of three sealers chosen at random. Demographic, clinical and radiographic variables were recorded at the start of, and during treatment. The periapical index (PAI) score was used to record the outcome of treatment, and applied in two different endpoint modes (END1 and END2) as the dependent variable for multivariate statistical analyses using logistic regression and the general model. The modes reflected increasing PAI scores (END1) and conventional success/failure assessment (END2). Dropouts were largely similar to the cases followed up. A total of 10 preoperative and peroperative variables were found to be significantly associated with treatment outcome by the multivariate analyses of either the total material or the NAP or CAP subgroups. Several of these were not significant in univariate analyses (e.g. the effect of sealer). Conventional success/failure analyses (END2) identified fewer of the influential variables and had low explanatory power, whereas PAI scores on an ordinal scale (END1) were most sensitive in identifying variables of influence on the treatment outcome.