We sought to investigate the simultaneous effect of apical periodontitis, instrumentation level, and density of root canal filling on endodontic treatment outcome. For this study, 200 endodontically treated teeth with 441 roots were used. A follow-up examination was conducted 4 ± 0.5 years postoperatively. Data were subjected to univariate and multivariate analysis. Periapical pathosis had the strongest effect on treatment outcome ( P <.0001). The instrumentation level (mean ± SEM of the working length) for successfully treated teeth/roots with normal preoperative pulp and periapex was farther away from the radiographic apex (1.23 ± 0.13mm) than for teeth/roots with an unsuccessful outcome (0.20 ± 0.09mm; P <.005). However, successfully treated teeth/roots with pulp necrosis and apical periodontitis had working length levels closer to the radiographic apex (0.55 ± 0.12 mm) than did teeth/roots with unsuccessful outcomes (1.73 ± 0.30mm; P<.001). In teeth/roots with apical periodontitis, a millimeter loss in working length increased the chance of treatment failure by 14%. The risk of failure was higher for a fair/poor density of obturation than for a good density for all diagnoses of periradicular status. Diseased periapex, level of working length relative to the radiographic apex, and fair/poor density all affect the outcome of endodontic treatment.