Background: Metabolic syndrome (MetS) is a combination of risk factors for cardiovascular disease and type 2 diabetes mellitus. The prevalence of MetS worldwide is increasing. There is no study investigating the economic burden of MetS, especially in developing countries, on medication-related expenditure. The aim of this study was to investigate the association of medication-related expenditures with MetS and to explore how physical activity (PA) may influence this association. Methods: A total of 620 participants, 50 years or older, randomly selected in the city of Bauru, Brazil. Participants were followed from 2010 to 2014, and data on health care expenditure were collected annually. PA questionnaire was applied at baseline, 2 (2012), and 4 (2014) years later. Results: Mean age was 64.7 (95% confidence interval, 64.1–65.3). MetS was associated with higher medication expenditure related to diseases of the circulatory (P <.01) and endocrine (P <.01) systems. MetS explained 17.2% of medication-related expenditures, whereas PA slightly attenuated this association, explaining 1.1% of all health care costs. Conclusion: This study demonstrates that MetS has a significant burden on health care expenditures among adults, whereas PA seems to affect this phenomenon significantly, but in low magnitude.