The success rate of inferior alveolar nerve block decreases exorbitantly in teeth with symptomatic irreversible pulpitis. The purpose of this prospective double blind randomized clinical trial was to evaluate the combined effect of oral premedication with ibuprofen and dexamethasone on the success rate of inferior alveolar nerve block in mandibular molars with symptomatic irreversible pulpits METHODS: Ninety-four adult patients actively experiencing pain and diagnosed with symptomatic irreversible pulpitis willingly participated in this study. Preoperative pain was recorded on the Heft Parker visual analog scale (VAS). Patients were randomly allocated to four different groups and received placebo (PLAg), 0.5 mg dexamethasone (DEXg), 800 mg ibuprofen (IBUg) and combination of 0.5mg dexamethasone and 800 mg ibuprofen (COMg). One hour after oral premedication, all patients received standard inferior alveolar nerve block containing 2% lignocaine with 1:200000 adrenaline. Access cavity preparation was initiated 15 minutes after administration of anesthesia. Pain scores were recorded on VAS after anesthesia, at dentin penetration to pulp chamber opening and on file placement. Success was defined as no or mild pain (0 mm-54 mm) throughout the procedure RESULTS: Chi square test was used for qualitative data comparison. One way ANOVA test and Post-hoc Boneferroni test showed statistically significant difference between COMg and the other 3 groups (P<0.001) CONCLUSIONS: Preoperative administration of combination of dexamethasone and ibuprofen improved the success rate of inferior alveolar nerve block in mandibular molars with symptomatic irreversible pulpitis.