Background: With limited evidence from a single center study [n=211 (11 with AO exposure)] reporting AO exposure as a risk factor for transformation, whether or not AO exposure increases the rate of transformation from MGUS to MM is unclear. Thus, we aimed to conduct a nation-wide study to determine the association between AO exposure and the risk of MGUS to MM progression. Methods: A retrospective, matched cohort study using data from the U.S. Veterans Health Administration system was conducted. Based on a power calculation, a random sample of MGUS patients with AO exposure was selected and 1:1 matched to those with MGUS without AO exposure (matching factors: age at MGUS diagnosis, race, body mass index categories). Data abstraction confirmed MGUS and MM diagnoses. In addition, information on date of diagnosis, MGUS subtype, and monoclonal protein (M-protein) values was performed. Patients were considered to have MGUS if they had M-protein detected on serum protein electrophoresis (SPEP) with immunofixation confirmation. The association of AO exposure with progression from MGUS to MM was examined using a multivariable Fine-Gray subdistribution hazard model with death as the competing event. The covariates included M-protein at MGUS diagnosis (>1.5, ≤1.5 g/dL [reference]), MGUS subtype (Immunoglobulin A, light chain, and Immunoglobulin G [reference]), and Charlson comorbidity score at MGUS diagnosis. A sensitivity analysis was conducted using inverse probability treatment weighted survival analysis to evaluate the robustness of the conclusion. Results: After excluding individuals with no confirmed MGUS or M MGUS subtype, a total of 563 MGUS patients with AO exposure and 563 matched controls were included. No statistically significant difference was observed in the progression of MGUS to MM between the AO exposed group and control group (adjusted hazard ratio (aHR) 0.78, 95% confidence interval (CI) 0.53 to 1.17). The sensitivity analysis demonstrated consistent results. Conclusions: Our carefully designed study does not show an association between AO exposure and progression of MGUS to MM in a national cohort of Veterans.