In 2016, unprecedented intense wildfires burned over 150,000 acres in the southern Appalachian Mountains in the United States. Smoke from these fires greatly impacted the region and exposure to this smoke was significant. A bidirectional case-crossover design was applied to assess the relationship between PM2.5 (a surrogate for wildfire smoke) exposure and respiratory- and cardiovascular-related emergency department (ED) visits in Western North Carolina during these events. For 0-, 3-, and 7-day lags, findings indicated a significant increase in the odds of being admitted to the ED for a respiratory (ORs: 1.055, 95% CI: 1.048-1.063; 1.083, 1.074-1.092; 1.066, 1.058-1.074; respectively) or cardiovascular event (ORs: 1.052, 95% CI: 1.045-1.060; 1.074, 1.066-1.081; 1.067, 1.060-1.075; respectively) for every 5μg/m3 increase in PM2.5 over a chosen cutpoint of 20.4μg/m3. For all endpoints assessed except for emphysema, there were statistically significant increases in odds from 5.1% to 8.3%. In general, this increase was most pronounced 3days after exposure. Additionally, individuals aged 55+ generally experience higher odds of heart disease at the 3- and 7-day lag points, and Black/African Americans generally experience higher odds of asthma at the 3-day lag point. In general, larger fires and increased numbers of fires within counties resulted in higher health burden at same day exposure. In a secondary analysis, the odds of an ED visit increased by over 40% in several cases among people exposed to days above the Environmental Protection Agency 24-hr PM2.5 standard of 35μg/m3. Our findings provide new understanding on the health impacts of wildfires on rural populations in the southeastern US.