Background: Approximately half of the women who take aromatase inhibitor (AI) therapy will develop joint pain, termed aromatase inhibitor-induced arthralgia (AIA). AIA becomes so painful that up to 20% of women will discontinue AI’s because of it. However, there is no standard treatment for this common, though poorly understood, problem. Methods: Using plasma samples from the MA.27 study, we identified 72 cases (with AIA) and 144 matched controls. We compared change in vitamin D level between baseline and 6 months in 204 cases and controls. We also correlated inflammatory cytokines with development of AIA. We measured 9 inflammatory cytokines which are implicated in low estrogen states, arthritis, and/or vitamin D deprivation -- Il-1, IL-6, TNF-α, IFNg, IL-10, IL-12p70, IL-17, IL-23, and CCL-20. Finally, we aimed to develop a multivariate model to predict for AIA using baseline factors such as vitamin D level, previously identified musculoskeletal SNP’s, age, BMI, and vitamin D receptor polymorphism. Results: After correcting for seasonal and geographic variation, the month 6 Vitamin D plasma levels increased by 4.52 ng/mL (p = 0.049), suggesting intake of vitamin D. However, there was no difference in the change in vitamin D levels between cases and controls. Elevated inflammatory cytokines were not correlated with the development of AIA. However, those with the Vitamin D receptor (VDR) FOK-I polymorphism were more likely to have a lower IL-1β level after 6 months of use as compared to those with wildtype VDR. In the multivariate model, the clinical factors listed above did not reliably predict development of AIA in this subset of patients. Conclusions: In this retrospective study, there is no correlation between vitamin D levels and the development of AIA. However, vitamin D receptor polymorphisms may explain some of the variation in individual responses to Vitamin D replacement. Patients with the Fok-I VDR polymorphism were more likely to have a significant reduction in IL-1β level.