Background: The etiology of multiple sclerosis (MS) is not fully understood, and the disease may be triggered or exacerbated by environmental risk factors, some of which may be modifiable. A better understanding of the geographic distribution of MS in the United States will help to assess these risk factors. Objectives: To examine the geographic distribution of MS in the United States and the association between latitude and disease prevalence. Methods: This cross-sectional study used a validated algorithm developed by the MS Prevalence Work Group to ascertain MS cases in Medicare, Medicaid, Veterans Administration and Optum claims data from the years 2008-2010. The combined dataset comprises 96 million individuals, including 727,344 estimated MS cases and their associated race, gender, age, and state characteristics. We obtained crude MS prevalence estimates by geography (state and latitudinal bands of 1 degree each), and geographic prevalence estimates adjusted for sex, age, and race and/or ethnicity using direct standardization with the 2010 U.S. total population. State latitude was defined as the mean center of population as defined by the US Census Bureau. Results: We observed a strong association between latitude and prevalence in the crude and direct-standardized results. With each degree of latitude, MS prevalence increased by 11.8 cases per thousand people (95% CI = 8.9-14.7, p<0.00001) in the crude prevalence estimates, and 7.1 cases per thousand people (95% CI=3.5-10.5, p<0.0001) in the direct-adjusted estimates. Pearson correlation coefficients between latitude and prevalence was r=0.49 and r=0.75 in the crude and direct-adjusted data, respectively. Significant associations between latitude and prevalence were observed across race, sex, age and insurance groups with some differences. Conclusions: MS prevalence in the United States increased significantly and non-monotonically with latitude after adjusting for race and ethnicity, age, and gender. These findings raise the possibility that environmental variables are associated with the occurrence of MS. Additional investigation is needed to determine the extent to which specific environmental or climactic characteristics might explain this geographic variation.