Background: The effects of exposure to fine particulate matter (PM2.5) during wildland fires are not well understood in comparison with PM2.5 exposures from other sources. Objectives: We examined the cardiopulmonary effects of short-term exposure to PM2.5 on smoke days in the United States to evaluate whether health effects are consistent with those during non-smoke days. Methods: We examined cardiopulmonary hospitalizations among adults ≥65 y of age, in U.S. counties (n=692) within 200km of 123 large wildfires during 2008-2010. We evaluated associations during smoke and non-smoke days and examined variability with respect to modeled and observed exposure metrics. Poisson regression was used to estimate county-specific effects at lag days 0-6 (L0-6), adjusted for day of week, temperature, humidity, and seasonal trend. We used meta-analyses to combine county-specific effects and estimate overall percentage differences in hospitalizations expressed per 10-μg/m3 increase in PM2.5. Results: Exposure to PM2.5, on all days and locations, was associated with increased hospitalizations on smoke and non-smoke days using modeled exposure metrics. The estimated effects persisted across multiple lags, with a percentage increase of 1.08% [95% confidence interval (CI): 0.28, 1.89] on smoke days and 0.67% (95% CI: −0.09, 1.44) on non-smoke days for respiratory and 0.61% (95% CI: 0.09, 1.14) on smoke days and 0.69% (95% CI: 0.19, 1.2) on non-smoke days for cardiovascular outcomes on L1. For asthma-related hospitalizations, the percentage increase was greater on smoke days [6.9% (95% CI: 3.71, 10.11)] than non-smoke days [1.34% (95% CI: −1.10, 3.77)] on L1. Conclusions: The increased risk of PM2.5-related cardiopulmonary hospitalizations was similar on smoke and non-smoke days across multiple lags and exposure metrics, whereas risk for asthma-related hospitalizations was higher during smoke days.