Purpose: Purpose of this study was to investigate the effects of stress, social support, and lifestyle on health-related quality of life among middle-aged women. Methods: One hundred forty three-middle aged women were recruited and completed questionnaires regarding their stress, social support, lifestyle and health-related quality of life. Data was analyzed by using descriptive statistics, t-test, ANOVA, and multiple regression. Results: Regression model was statistically significant (F=24.80, p<.001) with 46% of adjusted R2. Stress showed to be a major factor influencing health-related quality of life in middle-aged women (p<.001) and the presence of chronic illness (p=.011) was noted as next in the result of a multiple regression analysis. Conclusion: The results suggest that nursing professionals should include strategies to reduce stress and to consider helping women with chronic illness when developing a health promotion program to increase health related quality of life for middle-aged women.