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Purpose The purpose of this study is to determine if using a combination of dexamethasone and dexmedetomidine (Dex-Dex) in a single-shot perineural local anesthestic provides an increased duration of pain relief and reduced consumption of opioids for patients undergoing shoulder surgery. Patients and methods This is a retrospective trial of adult patients without major comorbidities undergoing elective, upper arm orthopedic procedures with regional nerve block for post-operative analgesia. Patients underwent nerve block with either 0.5% ropivacaine or 0.2% ropivacaine with 5mg dexamethasone and 25mg dexmedetomidine (“dex-dex”). Patients were assessed in 1-week intervals for two weeks for duration of block analgesia, pain scores, and opioid use. Results 31 patients were included, 12 controls and 19 in the dex-dex group. These patients underwent one of arthroscopic rotator cuff repair, reverse total shoulder repair or repair of humerus fractures. Dex-dex blocks provided significantly longer analgesia (median block time 3.5 versus 1.5 days, p Conclusion Preoperative single-shot interscalene nerve blocks with preservative-free dexamethasone and dexmedetomidine added as adjuvants to ropivicaine provide approximately two additional days of benefit versus ropivicaine alone. Additionally, postoperative opioid consumption is reduced.