Introduction: This randomized clinical trial assessed the effect of preoperative intraoral cryotherapy application on the success rate of inferior alveolar nerve blocks (IANBs) in patients with symptomatic irreversible pulpitis (SIP). Methods: One hundred four patients with SIP were randomly distributed into 2 groups: control and cryotherapy groups. In the control group, patients received an IANB injection with 2% lidocaine. In the cryotherapy group, intraoral cryotherapy application was performed for 5 minutes after the IANB. Endodontic therapy was then conducted 15 minutes after the IANB injection. If the patients reported moderate or severe pain during the procedure, the IANB was defined as "unsuccessful," and a supplementary injection was administered. Results: All patients reported profound lip numbness. The overall success rate for the IANBs was 43.3%. In the cryotherapy group, the success rate of the IANBs was 55.8%, whereas in the control group it was 30.8% (P < .05). Conclusions: Intraoral cryotherapy application increased the success rate of IANBs in mandibular molar teeth with SIP. However, supplemental anesthesia techniques may still be required to provide profound pulpal anesthesia in many cases.