Introduction: Anesthetic efficacy of the inferior alveolar nerve block (IANB) for mandibular molars decreases in patients with symptomatic irreversible pulpitis (SIP). It was hypothesized that premedication with non-steroidal anti-inflammatory drugs (NSAIDs) might improve the success rates of anesthesia in such patients.Methods: Sixty-eight patients who had their mandibular first or second molar diagnosed with SIP participated in the study. The patients randomly received, in a double blind manner, identical clear packets of either 50 mg diclofenac potassium or placebo 30 minutes before IANB anesthesia. Lip numbness was ascertained as well as response to cold test 15 minutes after the block was recorded on Heft Parker Visual Analogue Scale (HP-VAS). If lip numbness occurred together with no or mild pain on cold endodontic access cavity preparation was initiated. Pain during treatment was recorded on HP VAS. Success was defined as no or mild pain.Results: Statistical analysis showed that success rates were 44.1% for the diclofenac potassium group and 35.3% for the placebo group, with no statistically significant difference between the two groups (P=0.442).Conclusion: Pre-medication with 50 mg diclofenac potassium may not affect the anesthetic efficacy of IANB for patients with symptomatic irreversible pulpitis in mandibular molars endodontically treated in one visit.