ABSTRACT: OBJECTIVE:The aim of this study was to compare the anesthetic efficacy of two volumes of articaine in conventional inferior alveolar nerve block (IANB) of mandibular molars with irreversible pulpitis, and in cases of anesthetic failure, its complementation with periodontal ligament injection (PDL). METHODS:Ninety patients with irreversible pulpitis in mandibular molars received conventional IANB with 1.8 mL or 3.6 mL of 4% articaine with 1:100,000 epinephrine. In cases of IANB failure, the same volumes were administered in the PDL. Presence of pulpal anesthesia and absence/presence of pain during pulpectomy were evaluated by electric pulp stimulation and verbal analogue scale, respectively. Relative risks (RR) with corresponding 95% confidence intervals (95% CI) were calculated for each outcome. RESULTS:27% and 42% of the patients achieved pulpal anesthesia following IANB with 1.8 mL and 3.6 mL, respectively (RR = 0.63, CI 95% 0.35 to 1.14, p = 0.12). Analgesia during pulpectomy was present in 64% and 73% of the patients, respectively, for 1.8 mL and 3.6 mL (RR = 0.87, CI 95% 0.66 to 1.16, p = 0.36). In cases of IANB failure, 75% and 42% of the patients that received 1.8 mL and 3.6 mL of PDL injection, respectively, achieved pulpal anesthesia (RR = 1.80, CI 95% 0.87 to 3.72, p = 0.11). During a new attempt at the pulpectomy procedure, analgesia was present in 69% and 75% of the patients, respectively, for 1.8 mL and 3.6 mL (RR = 0.91, CI 95% 0.57 to 1.45, p = 0.71). CONCLUSION:Increasing the volume from 1.8 mL to 3.6 mL of the 4% articaine with 1:100,000 epinephrine in the IANB and in the PDL, did not significantly increase the success rate of pulpal anesthesia and clinical analgesia during the pulpectomy procedure. Therefore, both volumes presented a similar efficacy, though neither resulted in effective pain control during irreversible pulpitis treatment. TRIAL REGISTRATION:ClinicalTrials.gov NCT02422823.