This study investigated the impact of demographic, social, and clinical factors on cancer patients' self-ratings of health-related quality of life (HRQL). The sample consisted of 1342 ethnically diverse individuals in treatment at four member institutions of the Eastern Cooperative Oncology Group (ECOG). Multivariable regression analyses were employed to determine the relationship between demographic variables (age, gender, race/ethnicity, socio-economic status (SES), living arrangement), clinical factors (performance status rating (PSR), disease type, disease stage), and social characteristics (spiritual beliefs, religious affiliation, relationship with physician) and five outcome measures of HRQL. The dependent variables, four dimensions of HRQL and overall HRQL, were measured by the Functional Assessment of Cancer Therapy-General (FACT-G) Quality of Life Measurement System. The results indicated that the full set of predictor variables accounted for 45% of the variance in patients' reporting of overall HRQL, 25% of the variance in physical well-being, 27% of the variance in social well-being, 30% of the variance in emotional well-being, and 41% of the variance in the area of functional well-being. The findings suggest that there are multiple factors that influence an individual's assessment of their HRQL and that these factors need to be considered in the management and treatment of culturally diverse cancer patients.