Previous research has suggested that, when compared to European Americans (EAs), African Americans (AAs) are at higher risk of metastatic disease at time of cancer diagnosis, and a higher risk of shorter survival. Although AA patients have reported worse physical health than EA patients, studies have rarely addressed whether racial/ethnic disparities exist on the social, emotional, and functional aspects of health-related quality of life. Five hundred and two AA and 396 EA patients with AIDS-related malignancies or breast, colon, head/neck, and lung cancers seeking treatment within the contiguous United States and Puerto Rico participated in the present study. Responses on the Functional Assessment of Cancer Therapy-General were analyzed for possible racial/ethnic disparities using multivariable regression models and item response theory modeling to detect differential item functioning. Differential item functioning was found in six items of the Functional Assessment of Cancer Therapy-General, indicating that AA and EA participants had different probabilities of responding to these items. Compared to EAs at the same level of health-related quality of life, AAs reported more severe symptomatology on items that reflected malaise and ability to work, and less severe symptomatology on items that reflected fatigue, treatment side effects, and outlook on life. At the subscale level, AAs reported poorer physical and social well-being, but better emotional well-being, than EAs. Similar to previous studies, AA patients reported poorer physical functioning than a comparable group of EA patients. Some items appear to be responded to differently by AAs and EAs, suggesting it is important to consider race/ethnicity when evaluating responses to questions about health-related quality of life.