Current management guidelines for the treatment of patients with Parkinson's disease (PD) are limited due to the lack of knowledge of factors that influence health-related quality of life (HRQL). To assess the HRQL of people with PD, and to systematically identify and evaluate those factors (other than disease severity and medication, which could have an impact), we undertook a cross-sectional, randomized selection, multicenter international survey of patients with PD, caregivers, and clinicians. Face-to-face interviews were conducted with subjects in six countries. Disease severity, medication, and other factors hypothesized to influence HRQL were assessed using a combination of specially developed questionnaires and validated instruments including the Parkinson's Disease Questionnaire-39 (HRQL), Hoehn and Yahr Stage (disease severity), and Beck's Depression Inventory (BDI; depression). Multiple linear regression models were used to demonstrate whether the factors investigated contribute significantly to HRQL. The results obtained indicated that Hoehn and Yahr stage and medication explained only 17.3% of the variability in HRQL of patients with PD, although both were significant (R2 = 0.173, P < 0.05). Other factors increased the explanatory power to adjusted R2 = 0.597, with BDI being the most significant predictor of variability in HRQL (adjusted R2 = 0.582; P < 0.001), followed by “Satisfaction with the explanation of the condition at diagnosis” and “Current feelings of optimism” (both P < 0.05). These factors, in addition to disease severity and medication, explain 59.7% of the variability in HRQL across the population. In conclusion, depression (as measured by the BDI) in PD, “satisfaction with the explanation of the condition at diagnosis” and “current feelings of optimism” have a significant impact on HRQL. The completion of this initial analysis is the first step towards developing management guidelines that truly influence the HRQL of patients with PD. © 2001 Movement Disorder Society.