Objective: The purpose of this population-based study was to analyse the association between the health-related quality of life and rural residence among Polish females, including variables related to social environment and clinical characteristics. Methods: The snowball recruitment method was used to invite 1,560 women aged 45-60 to participate in the study. Participants received a questionnaire about demographic characteristics, environmental and work stress, use of anxiolytic-hypnotic medications and self-reported quality of life based on the SF-36 form. Univariate and multivariate analysis was carried out by means of a logistic regression model. Results: We found worse physical health and better mental health among women living in rural areas compared to those from urban settings. The rural residence was an independent predictor for poor physical health (below 25 percentile) odds ratio [OR] 1.6 95%, confidence interval [CI] 1.17-2.2). Living in rural areas was also associated at the borderline level of statistical significance, with reduction of risk of low quality of life in mental health (OR = 0.75; 95% CI = 0.55-1.02). According to other results from multivariate analysis, being retired, receiving social pension, long duration of illness symptoms, and consulting a medical specialist were the risk factors of reported bad physical health. Higher education and access to medical specialist protects against having a bad quality of life related to mental health. Being given the sack, stress at work, feeling anger, and long duration of symptoms are the risk factors of poor mental health. Conclusion: The rural residence is strongly associated with environmental and psychosocial factors in women aged 40-65.