Indiana University-Purdue University Indianapolis (IUPUI) / Introduction: Profound pulpal anesthesia is not always adequate in mandibular teeth after the administration of local anesthesia, especially in the presence of irreversible pulpitis. Failure to achieve anesthesia has been seen in 30–80% of patients in teeth with a diagnosis of irreversible pulpitis. Onpharma™ developed an FDA-approved device that uses sodium bicarbonate to buffer a standard local anesthetic (LA) solution so that its pH may become closer to its pKa. Claims have been made that buffering a local anesthetic increases the anesthetic’s effect. Previous studies on the anesthetic efficacy of Onpharma’s Onset buffering system were inconclusive and may be dependent on the techniques used. Objectives: The aim of this study is to determine whether a buffered local anesthetic can lead to more profound and faster pulpal anesthesia in mandibular molars diagnosed with symptomatic irreversible pulpitis as compared to a standard, unbuffered local anesthetic. Materials and Methods: 40 total subjects completed the study. Screened and eligible subjects with a mandibular molar diagnosed with symptomatic irreversible pulpitis were randomly allocated into 2 groups so 1 group received a total of 3 cartridges of a standard, unbuffered 2% lidocaine with 1:100,000 epinephrine via inferior alveolar nerve block (IANB) followed by supplemental buccal and lingual infiltrations, while the other received the equivalent yet buffered formulation. An electronic pulp tester (EPT) was used to objectively determine baseline pulpal status of the affected tooth, followed by 2-minute interval testing following the administration of all local anesthesia. The onset of pulpal anesthesia was defined by the first of 2 consecutive EPT=80 readings, and the endodontic treatment could begin. Profound pulpal anesthesia was ultimately determined if the patient reported a comfortable pulpotomy as reflected on the Wong-Baker FACES Visual Analog Scale. Null Hypothesis 1: Subjects possessing mandibular molars diagnosed with symptomatic irreversible pulpitis will not achieve pulpal anesthesia more profoundly using buffered 2% lidocaine w/ 1:100,000 epinephrine in comparison to the standard, unbuffered anesthetic formulation. Null hypothesis 2: Subjects possessing mandibular molars diagnosed with symptomatic irreversible pulpitis will not achieve pulpal anesthesia faster using buffered 2% lidocaine w/ 1:100,000 epinephrine in comparison to the standard, unbuffered anesthetic formulation. Results: We observed a local anesthetic success rate of 45% in the buffered group, 70% in the unbuffered group, and ultimately 57.5% between both groups. The findings further indicate that the VAS scores after pulpotomy is significantly different between the 2 groups (p=0.019), with the unbuffered group having a more profound mean VAS score of 1.2 (as opposed to a buffered mean of 3.1). Regarding the time of onset for pulpal anesthesia, there was no statistically significant difference noted between the buffered and unbuffered groups. Conclusion: Based on the findings of this study, the null hypothesis 1 cannot be rejected since unbuffered 2% lidocaine with 1:100,000 epinephrine had a statistically significant increase in profound pulpal anesthesia compared to the buffered equivalent. The null hypothesis 2 cannot be rejected since there was no evidence of a significant difference in the time to pulpal anesthesia between the buffered and unbuffered groups.