Aim The purpose of this study was to compare the outcome of nonsurgical root canal treatment (RCT) in patients with autoimmune diseases (AD) with the outcome in patients without AD. The null hypothesis was: there is no difference in the outcomes of RCT regardless of the patient group. Results were also compared among AD subgroups: inflammatory bowel disease (IBD), rheumatoid arthritis (RA), and psoriasis (Ps).Methodology Data were obtained from a database using codes corresponding to the National Health Insurance Dental Fee Schedule. Patients diagnosed with AD who received primary RCT at the Veterans Health Service Medical Center from 2010 to 2022 formed the study group. Controls were matched using propensity score matching for age, sex, arch type, and tooth type. Preoperative periapical lesions, canal filling quality, and RCT outcomes were assessed through radiographs, including panoramic, periapical, and cone-beam computed tomography images. Outcomes were evaluated at approximately 1 year and at maximum follow-up. Chi-square tests and logistic regression were used to evaluate associations between AD and RCT success.Results The study included 203 ad patients (317 teeth) and 203 controls (312 teeth). At 1 year, success rates were 69.4% in AD patients and 73.7% in controls (p = 0.268). Within the AD group, success rates were 64.6% for IBD, 75.3% for RA, and 73.2% for Ps. Patients with IBD showed only statistical significance (p = 0.025). The mean observation duration for the maximum follow-up was approximately 50 months. Long-term success rates were 61.5% for AD and 66.0% for controls (p = 0.207). Multivariate logistic regression analysis indicated that arch type, tooth type, and the presence of preoperative apical lesions were significant factors influencing the outcome of RCT. Comparing the 1-year and long-term outcomes, IBD, RA, and Ps showed a similar trend of decreased success rates, although the differences were not statistically significant.Conclusions RCT success rates in patients with AD were comparable to those of controls. Multivariable analysis revealed that clinical factors were the primary predictors of success, rather than the presence of AD. Therefore, high-quality clinical procedures are the critical factor for favorable outcomes in AD patients.