Background/objectives This randomized controlled crossover clinical trial aimed to compare the anesthetic efficacy between intraosseous and buccal infiltration techniques as a primary anesthesia for mandibular first molars. Materials and methods Twenty adult subjects randomly received intraosseous injection of 1.7 ml 4% articaine with 1:100,000 epinephrine or buccal infiltration of 3.4 ml 4% articaine with 1:100,000 epinephrine at 2 separate appointments. The mandibular first molars were tested for anesthesia with an electric pulp tester at 3-minute cycles for 60 minutes after the injections. Pain ratings for each injection were recorded. The data were analyzed using the McNemar and Wilcoxon signed ranks tests. Results There was no significant difference (p = 0.250) in success rate between the intraosseous injections (95%) and buccal infiltrations (80%). However, the onset of pulpal anesthesia was significantly faster with the intraosseous injections (p = 0.004). No significant differences were foundfor injection or postinjection pain (p > 0.05). Conclusion The success rate of buccal infiltration using two cartridges of 4% articaine with 1:100,000 epinephrine is comparable to that of intraosseous injection using a single cartridge of 4% articaine with 1:100,000 epinephrine in asymptomatic mandibular first molars. Both techniques can be useful alternatives for inducing mandibular first molar anesthesia.