Parkinson’s disease has a negative impact on health-related quality of life in Parkinson’s disease patients. Depression, cognitive impairment, coping strategies, dyskinesia, gait disorders and complications of dopaminergic drugs are the variables that most affect health-related quality of life. The ecological model of human development focuses attention on both individual and social environmental factors as targets for health interventions. From this perspective, the aim of this cross-sectional survey was to evaluate the influence of gender, family size and perceived autonomy on health-related quality of life in Parkinson’s disease patients in northeastern Sicily, Italy. Ninety Parkinson’s disease patients, attending the Movement Disorders Clinic at IRCCS Centro Neurolesi “Bonino-Pulejo” (Messina), were consecutively enrolled. The Unified Parkinson Disease Rating Scale motor subscale (UPDRS-Ⅲ) scores, the Parkinson Disease Questionnaire-39 Item scores (as a disease-specific measure of health-related quality of life), scores on the Short Form (36) Health Survey Questionnaire (as a generic measure), and answers to a brief checklist were recorded. A total of 85 Parkinson’s disease patients (49% males and 51% females; mean age 70.8 ± 8.6 years; mean UPDRS-Ⅲ 24.15 ± 6.55; mean disease duration 5.52 ± 4.65 years) completed the booklet of questionnaires. In the multivariate regression analysis, we included clinical and social variables as independent predictors of health-related quality of life. Our results suggest a potential compounding effect of ecological intrapersonal and interpersonal levels on health-related quality of life outcomes. Gender, self-evaluated autonomy and family size significantly impacted health-related quality of life. If quality of life is used as an indicator of treatment outcomes, an ecological perspective of the case history will be important to disclose relevant prognostic information and trigger personalized health care interventions. Parkinson’s disease has a negative impact on health-related quality of life in Parkinson’s disease patients. Depression, cognitive impairment, coping strategies, dyskinesia, gait disorders and complications of dopaminergic drugs are the variables that most affect health-related quality of life. The ecological model of human development as attention for both individual and social environmental factors as targets for health interventions. From this perspective, the aim of this cross-sectional survey was to evaluate the influence of gender, family size and perceived autonomy on health-related quality of life in Parkinson’s disease patients in northeastern Sicily, Italy. Ninety Parkinson’s disease patients, attending the Movement Disorders Clinic at IRCCS Centro Neurolesi “Bonino-Pulejo ” (Messina), were consecutively enrolled. The Unified Parkinson Disease Scale Scale motor subscale (UPDRS -Ⅲ) scores, the Parkinson Disease Questionnaire-39 Item scores (as a disease-specific measure of health-related quality of life, scores on the Short Form (36) Health Survey Questionnaire (as a generic measure), and answers to a brief checklist were recorded. A total of 85 Parkinson’s disease patients (49% males and 51% mean age 70.8 ± 8.6 years; mean UPDRS-Ⅲ 24.15 ± 6.55; mean disease duration 5.52 ± 4.65 years) completed the booklet of questionnaires. we include clinical and social variables as independent predictors of health-related quality of life. Our results suggest a potential compounding effect of ecological intrapersonal and interpersonal levels on health-related quality of life outcomes. Gender, self-evaluated autonomy and family size significantly impacted health-related quality of life. as an indicator of treatment outcomes, an ecological perspective of the case history will be important to disclose relevant prognostic information and trigger personalized health care interventions.