BACKGROUND: Experimental evidence and studies of children and adolescents suggest that ambient fine particulate matter [particulate matter ≤2:5 lm in aerodynamic diameter (PM2:5)] air pollution may be obesogenic, but the relationship between PM2:5 and the risk of body weight gain and obesity in adults is uncertain. OBJECTIVES: Our goal was to characterize the association between PM2:5 and the risks of weight gain and obesity. METHODS: We followed 3,902,440 U.S. Veterans from 2010 to 2018 (median 8.1 y, interquartile range: 7.3–8.4) and assigned time-updated PM2:5 exposures by linking geocoded residential street addresses with satellite-based estimates of surface-level PM2:5 mass (at ∼ 1-km2 resolution). Associations with PM2:5 were estimated using Cox proportional hazards models for incident obesity [body mass index (BMI) ≥ 30 kg=m2 ] and a 10-lb increase in weight relative to baseline and linear mixed models for associations with intra-individual changes in BMI and weight. RESULTS: A 10-lg=m3 higher average annual PM2:5 concentration was associated with risk of incident obesity [n = 2,325,769; hazard ratio (HR) =1:08 (95% CI: 1.06, 1.11)] and the risk of a 10-lb (4:54 kg) increase in weight [HR = 1:07 (95% CI: 1.06, 1.08)] and with higher intra-individual changes in BMI [0:140 kg=m2 per year (95% CI: 0.139, 0.142)] and weight [0:968 lb=y (95% CI: 0.955, 0.981)]. Nonlinear exposure– response models indicated associations at PM2:5 concentrations below the national standard of 12 lg=m3. As expected, a negative exposure control (ambient air sodium) was not associated with obesity or weight gain. Associations were consistent in direction and magnitude across sensitivity analyses that included alternative outcomes and exposures assigned at different spatial resolutions. DISCUSSION: PM2:5 air pollution was associated with the risk of obesity and weight gain in a large predominantly male cohort of U.S. Veterans. Discussions about health effects of PM2:5 should include its association with obesity, and deliberations about the epidemiology of obesity should con-sider its association with PM2:5. Investigation in other cohorts will deepen our understanding of the relationship between PM2:5 and weight gain and obesity. https://doi.org/10.1289/EHP7944.