This study sought to quantify the incidence of root canal treatment (RCT) failure and identify its predictors in root canals that were performed or referred by general dentistry practices in a practice-based research network (PBRN). This retrospective cohort study involved 174 endodontically treated teeth. Mean duration from initial therapy to follow-up was 8.6 years. Permanent restorations were ultimately placed in 89% of teeth, although 18% of teeth were ultimately extracted anyway. Receiving a permanent restoration was a significant predictor of treatment failure (in other words, patients who did not receive a permanent restoration were more likely to experience RCT failure), whether failure was determined clinically or radiographically. This study of PBRN practices suggests a higher failure rate compared with studies that utilized highly controlled environments or populations with high levels of dental insurance.