A hierarchical multiple linear regression approach (N = 761) was used to identify pertinent factors which influence health-related quality of life (HRQL) reports among Hispanic and African-American cancer patients. The independent variables include: performance status, disease site, disease stage, mode of administration, socio-economic status (SES), gender, age, living arrangement, race/ethnicity, religious affiliation, insurance status, and spiritual beliefs. The outcome measures, five subscales of HRQL (physical well-being, social well-being, satisfaction with treatment, emotional well-being, functional well-being) and overall HRQL (sum of the five subscales), were estimated using the Functional Assessment of Cancer Therapy (FACT) Scales. This study identified performance status and spiritual beliefs as consistent predictors of overall HRQL. This study also found no significant effects of SES, mode of administration, gender age, living arrangement and insurance status on the reporting of overall HRQL. Spiritual beliefs and performance status are important determinants of HRQL across a diverse group of cancer patients.