Root canal treatment (RCT) is commonly performed surgery and persistent pain is known to occur, but little is known about how these patients are affected by this pain. While biopsychosocial mechanisms are thought to be associated with the development of such pain, similar to persistent pain following surgery in other body sites, little is known about the baseline predictors for persistent pain. We assessed the frequency of persistent pain 6 months following RCT, measured the impact this pain had on patients, and determined predictive factors for persistent tooth pain in a multi-center prospective cohort study conducted within the National Dental Practice-Based Research Network. Of 708 patients enrolled, 651 (91.9%) provided follow-up data, with 65 (10.0%) meeting criteria for pain 6 months following RCT. On average, these patients reported their pain as mild to moderate in intensity, present for about 10 days in the preceding month, and minimally interfered with daily activities. After adjusting for type of dental practitioner and patient age, gender and household income, pain duration over the week prior to RCT significantly increased the risk of developing persistent pain (odds ratio [OR]=1.19 per 1 day increase in pain duration, 95% confidence interval [CI]: 1.07–1.33), whereas optimism about the procedure reduced the risk (OR=0.39, 95% CI: 0.22–0.67). Our data suggest that persistent pain following RCT is fairly common, but generally does not have a large impact on those experiencing it. Furthermore, patient age and gender did not predict persistent pain, while pre-operative pain duration and the patient’s expectation did.