Introduction: Several variables may influence anesthesia success in maxillary molars. This investigation was conducted to evaluate the effect of root length on the success rate of infiltration injections of 2% lidocaine with 1:80,000 epinephrine. Methods: One hundred maxillary first molars with irreversible pulpitis were treated. After the administration of a buccal infiltration injection of 2% lidocaine with 1:80,000 epinephrine, the patients’ pain during dentin cutting, pulp exposure, and root canal instrumentation were evaluated using the Heft-Parker visual analog scale. No or mild pain was considered as success. Data were analyzed by the point-biserial correlation test and receiver operating characteristic curve analysis. Results: Overall, 61% of the teeth had successful anesthesia after the administration of a single buccal infiltration injection of anesthetic solution. The point-biserial correlation test showed that the teeth that had palatal and distobuccal roots with longer root lengths showed significantly higher anesthesia failure (P < .05). However, receiver operating characteristic curve analysis did not show a clinically useful cutoff point of root length corresponding with anesthesia failure. Conclusions: Maxillary first molars having irreversible pulpitis with longer roots may have more anesthesia failures after a single buccal infiltration injection with 2% lidocaine and 1:80000 epinephrine.