Background: Little is known about risk factors associated with poor health among employees with COPD living in Central Appalachia. Purpose: Determine variability in health distress based on risk factors, including race and income, among employees with COPD from Central Appalachian U.S. States. Methods: 2016–2017 BRFSS data were analyzed from employed adults with COPD living in KY, NC, TN, and WV (N = 1,326). Health risks included (1) comorbidities; (2) substance use/abuse; and (3) limited healthcare access as predictors of mental and physical distress, with race and income entered as covariates. Results: Respondents reporting several comorbidities were more likely to report physical and mental distress compared to those without comorbidities. Workers who used e-cigarettes on some versus no days were more likely to report physical distress. Those reporting cost preventing access to medical care versus no cost barriers were more likely to report physical and mental distress. Low-income workers were more likely than higher-income workers to report distress. Discussion: Comorbidities, e-cigarettes, and high medical costs are potential causes of occupation-related disability among employees with COPD working in Central Appalachian U.S. States. Translation to Health Education Practice: Worksite interventions should address risks negatively associated with health outcomes among workers with COPD from Central Appalachia.