The authors investigated whether short-term effects of fine particulate matter with an aerodynamic diameter ≤2.5 μm (PM2.5) on risk of cardiovascular and respiratory hospitalizations among the elderly varied by region and season in 202 US counties for 1999–2005. They fit 3 types of time-series models to provide evidence for 1) consistent particulate matter effects across the year, 2) different particulate matter effects by season, and 3) smoothly varying particulate matter effects throughout the year. The authors found statistically significant evidence of seasonal and regional variation in estimates of particulate matter effect. Respiratory disease effect estimates were highest in winter, with a 1.05% (95% posterior interval: 0.29, 1.82) increase in hospitalizations per 10-μg/m3 increase in same-day PM2.5. Cardiovascular diseases estimates were also highest in winter, with a 1.49% (95% confidence interval: 1.09, 1.89) increase in hospitalizations per 10-μg/m3 increase in same-day PM2.5, with associations also observed in other seasons. The strongest evidence of a relation between PM2.5 and hospitalizations was in the Northeast for both respiratory and cardiovascular diseases. Heterogeneity of PM2.5 effects on hospitalizations may reflect seasonal and regional differences in emissions and in particles’ chemical constituents. Results can help guide development of hypotheses and further epidemiologic studies on potential heterogeneity in the toxicity of constituents of the particulate matter mixture.