The limited studies on the effect of buffering on the clinical efficacy of articaine have reported controversial results. The purpose of this study was to clinically compare the pain of injection, anesthetic success, onset, and duration of pulpal anesthesia of buffered 4% articaine with epinephrine 1:100000 versus a non-buffered 4% articaine with epinephrine 1:100000 formulation for buccal infiltration of the mandibular first molar. Sixty-three volunteers were enrolled in the study. All volunteers received two injections consisting of a single mandibular first molar buccal infiltration with 1.8 ml of 4% articaine with epinephrine 1:100000 and 1.8 ml of 4% articaine with epinephrine 1:100000 buffered with 8.4% sodium bicarbonate. The infiltrations were applied in two separate appointments spaced at least one week apart. After injection of the anesthetic solution at the examined site, the first molar was pulp-tested every 2 min for the next 60 min. Successful pulpal anesthesia was recorded in 69.8% of cases using non-buffered articaine solution and 76.2% of cases using buffered articaine solution, with no significant difference between the formulations (P = 0.219). The mean time of anesthesia onset for the volunteers with successful anesthetic outcome in both formulations (n = 43) was 6.6 ± 1.6 min for the non-buffered articaine solution and 4.5 ± 1.6 min for the buffered solution, which differed significantly (P = 0.001). In the same volunteers, the mean duration of pulpal anesthesia was 28.4 ± 7.1 min for non-buffered articaine solution and 30.2 ± 8.5 min for buffered articaine solution, with no significant difference between the formulations (P = 0.231). Considering the pain of injection, regardless of the anesthetic success, the mean values of VAS were 11.3 ± 8.2 mm for the non-buffered articaine solution and 7.8 ±6.5 mm for the buffered articaine solution, which differed significantly (P = 0.001 < 0.05). According to the present study, 4% articaine with epinephrine can benefit from buffering and provide better anesthetic behavior, with improved onset and less pain during injection.