This randomized, active-controlled, double-blind, prospective clinical trial evaluated the anesthetic efficacy of 2% lidocaine with 1:200,000 epinephrine versus an admixture of 2% lidocaine with 1:200,000 epinephrine and 1 mL of 4 mg dexamethasone (Twin mix) for inferior alveolar nerve blocks (IANBs) in patients with symptomatic irreversible pulpitis (SIP) of the mandibular molars. Seventy-eight patients with SIP of mandibular molars were randomly allocated to the 2 groups of 39 subjects. All patients were required to have profound lip numbness within 10 minutes of local anesthetic deposition. The efficacy of pulpal anesthesia was confirmed by absence of pain or mild pain (Heft-Parker visual analogue scale ≤54 mm) during access cavity preparation and placement of glide path files. The collected data were subjected to independent t test, chi-square test, and Fisher exact test using SPSS software version 20.0 at a significance level of 0.05. IANB success rates for the lidocaine group and the Twin mix group was 66% and 68% respectively, which was not a statistically significant difference (p > .05). This study demonstrated that the anesthetic efficacy of Twin mix was equivalent to 2% lidocaine for IANBs in teeth with SIP.