Background Multiple sclerosis (MS) is a presumed autoimmune disease caused by genetic and environmental factors. It is hypothesized that environmental exposures (such as air and water quality) trigger the innate immune response thereby activating a pro-inflammatory cascade. Objective To examine potential environmental factors in pediatric MS using geographic information systems (GIS). Methods Pediatric MS cases and healthy controls were identified as part of an ongoing multicenter case-control study. Subjects’ geographic locations were mapped by county centroid to compare to an Environmental Quality Index (EQI). The EQI examines 5 individual environmental components (air, land, water, social, built factors). A composite EQI score and individual scores were compared between cases and controls, stratified by median proximity to enrollment centers (residence <20 or ≥20 miles from the recruiting center), using logistic regression. Results Of the 287 MS cases and 445 controls, 46% and 49% respectively live in areas where the total EQI is the highest (worst environmental quality). Total EQI was not significantly associated with the odds for MS (p = 0.90 < 20 miles from center; p = 0.43 ≥ 20 miles); however, worsening air quality significantly impacted the odds for MS in those living near a referral center (OR = 2.83; 95%CI 1.5, 5.4) and those who reside ≥ 20 miles from a referral center (OR = 1.61; 95%CI 1.2, 2.3). Conclusion Among environmental factors, air quality may contribute to the odds of developing MS in a pediatric population. Future studies will examine specific air constituents and other location-based air exposures and explore potential mechanisms for immune activation by these exposures.