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Abstract: Breast cancer patients receiving endocrine therapy with aromatase Inhibitors (AIs) often experience musculoskeletal and joint‐related side effects. The purpose of this study was to evaluate the effect of Vitamin B12 supplements on musculoskeletal symptoms such as pain and arthralgias induced by AIs and to correlate response with serum and inflammatory biomarkers. Upon receiving approval by the Institutional Review Board (IRB), the majority of the patients consented into the study were treated at the Texas Tech Breast Care Center. Included were patients who had a diagnosis of invasive breast cancer (Stages I‐III), and were experiencing significant musculoskeletal symptoms associated to AIs. Only patients with an average pain score ≥ 4, as assessed by the Brief Pain Inventory‐Short Form (BPI‐SF) questionnaire, were included in the study. Participants received 2500 mcg of sublingual vitamin B12 daily for 90 days. Assessments at baseline and at 3 months included: BPI‐SF pain scores, the impact on quality of life determined by Functional Assessment of Cancer Therapy–Endocrine Symptoms (FACT‐ES), and correlative serum markers relative to baseline (a pre‐post study). A total of forty‐one patients were enrolled. Average pain scores were improved by 34% (P < .0001) at 3 months compared to baseline. In addition, a 23% improvement in worst pain was noted (P = .0003). Analysis of the results for the FACT‐ES scoring showed improvement on all scales. No significant adverse events were observed. Decrease in pain score was correlated with increased serum B12 levels. This study suggests that Vitamin B12 reduces pain and improves quality of life for patients taking AIs who experienced AI‐related musculoskeletal symptoms. If confirmed in large randomized prospective trials, Vitamin B12 would be a safe and cost‐effective option for the treatment of AI‐related musculoskeletal symptoms. [ABSTRACT FROM AUTHOR]