The purpose of this study was to examine the dose-response relationship between physical activity (PA) and health-related quality of life (HRQOL) among adults with and without limitations. We dichotomized HRQOL as a parts per thousand yen14 unhealthy (physical or mental) days (past 30 days), or < 14 unhealthy days. By using a moderate-intensity minute equivalent, PA categories were as follows: inactive, 10-60, 61-149, 150-300, and > 300 min/week. Persons with limitations reported having problems that limited their activities or required use of special equipment. Age-adjusted prevalence estimates and logistic regression analyses were performed with 2009 Behavioral Risk Factor Surveillance System data (n = 357,665), controlling for demographics, BMI, smoking, and heavy alcohol use. For adults without limitations, the odds of a parts per thousand yen14 unhealthy days were lower among adults obtaining any PA (10-60 min/week, AOR = 0.79, 95 % CI 0.70, 0.88), compared with those inactive. A quadratic trend (P < 0.001) indicated enhanced HRQOL with each PA level, but improvements were less marked between lower and upper sufficient PA categories (150-300 and > 300 min/week). Because of a significant age interaction, persons with limitations were stratified by age (18-34, 35-64, and 65+ years). Findings for persons aged 35 years or older with limitations were similar to those without limitations. Lower odds of poor HRQOL for persons aged 18-34 years with limitations were associated with recommended levels of PA (150-300 min/week; AOR = 0.61, 95 % CI 0.43, 0.88 and > 300 min/week; AOR = 0.58, 95 % CI 0.43, 0.80). PA is positively associated with HRQOL among persons with and without limitations.