To examine the prevalence and association of health-related quality of life (HRQOL) with trying to lose weight and with weight loss practices (eating fewer calories, physical activity, and both) among overweight and obese U.S. adults >/= 20 years of age. This study used data from the 2001 to 2002 National Health and Nutrition Examination Survey, a continuous annual survey of the civilian non-institutionalized U.S. population. This analysis included those > or = 20 years of age with BMI > or = 25 (n = 2578) who responded to four standard HRQOL measures that assessed general health status and recent physical health, mental health, and activity limitation. Among obese men, but not women, there were significant increasing linear trends in the adjusted prevalence of trying to lose weight as physically unhealthy and activity limitation days increased. Regardless of BMI or HRQOL, reducing calories was a common weight loss practice (66% to 86%). Except for recent activity limitation, respondents with BMI > or = 35 did not generally differ by HRQOL level in the attainment of recommended physical activity either alone or in combination with reduced calories, whereas those in the BMI 25 to 34.9 groups often differed significantly by HRQOL level. Specifically, increased unhealthy or activity limitation days were associated with reduced prevalence of attained physical activity. Our findings indicate an association between trying to lose weight and a greater number of unhealthy days reported by obese men, suggesting that these men may be influenced by traditional clinical weight-loss counseling that is prompted by weight and comorbidity, whereas women had a high prevalence of trying to lose weight irrespective of weight and HRQOL. Assessment of HRQOL, especially measures that evaluate physical domains, could provide subjective information to assist with weight counseling.