Archival data (N = 123,506) from the CDC’s 2003 Behavioral Risk Factor Surveillance System was used in the present study to examine the relationships among body mass index (BMI), physical activity, and health-related quality of life (HRQOL) in employed adults in the United States. Results revealed that 40.0% of the respondents were nonoverweight (BMI ≤ 24.9), 36.8% were overweight (BMI = 25.0--29.9), 15.3% were obese (BMI = 30.0--34.9), and 7.9% were severely obese (BMI ≥ 35.0). More than half (51.5%) of the respondents reported no physical activity or had an insufficient amount to meet the moderate or vigorous physical activity recommendation, 33.0% met the moderate or vigorous physical activity recommendation, and 15.5% met both the moderate and vigorous physical activity recommendations. More importantly, this study found significant differences in each of the HRQOL domains (i.e., perceived health status, physical health, mental health, and poor health) across the different BMI classifications and physical activity statuses. Perceived health status decreased across the BMI classifications and increased across the physical activity statuses. The number of unhealthy days as a result of physical, mental, or poor health status increased across the BMI classifications and decreased across the physical activity statuses. There was also a significant difference in perceived health status and the number of unhealthy days in each HRQOL domain for physical activity status within each BMI classification. Given the impact of obesity on health care costs, absenteeism, presenteeism, and work limitations of employees, furthering our understanding of how HRQOL is affected by BMI and physical activity will be useful information for employers as well as health promotion professionals in the workplace.