Background: There has been an increased interest in the study of physical activity and its relationship with quality of life (QOL) and health-related quality of life (HRQL) in chronic disease conditions. The investigations have used either generic or disease-targeted instruments for measuring QOL and HRQL, but have not examined differences in the associations as a function of the types of instruments. Purpose: The present study examined the associations among physical activity, QOL, and HRQL using generic and disease-targeted instruments in persons with multiple sclerosis (MS). Methods: Participants were 292 individuals with MS who wore an accelerometer for 7 days and then completed the Godin Leisure-Time Exercise Questionnaire (GLTEQ), Multiple Sclerosis Impact Scale-29 (MSIS-29), Leeds Multiple Sclerosis Quality of Life Scale (LMSQOL), Short Form-12 Health Survey (SF-12), and Satisfaction With Life Scale (SWLS). Results: Accelerometer counts and GLTEQ scores had similarly sized correlations with scores from generic (SF-12) and the disease-specific (MSIS-29) measures of HRQL and generic (SWLS) and the disease-specific (LMSQOL) measures of QOL. Path analysis indicated a similar pattern of directional relationships between accelerometer counts and GLTEQ scores with physical and mental HRQL and, in turn, physical and mental HRQL with QOL using generic and disease-targeted instruments. Conclusions: Our results suggest that in cross-sectional analysis, physical activity is similarly related with QOL and HRQL using generic and disease-targeted instruments in persons with MS. © 2008 The Society of Behavioral Medicine.