Purpose: Limited epidemiological investigations have examined the association of yoga participation and health-related quality of life (HRQOL), which was the purpose of this study. Methods: Data from the 2001-2006 National Health and Nutrition Examination Survey were employed (n = 14,455). Yoga participation and HRQOL were assessed via self-report. Results: After adjustments, in the entire sample (n = 14,455), yoga participation was not associated with better HRQOL (βadjusted = −0.17; 95% CI: −0.60-0.24; P = 0.40). When stratified by those above the mean age (≥ 45 years; Ntotal = 7,072; Nyoga = 67), yoga participation was associated with better HRQOL (βadjusted = –0.69; 95% confidence CI: –1.29 to -0.09; P=0.02). Conclusion: In this national sample, there was some suggestive evidence of a favorable association of yoga participation and HRQOL among middle-age and older adults.