Health-related quality of life is an important outcome in cancer care. A few studies indicate that health literacy influences cancer patients' health-related quality of life, but additional investigation is needed. The authors examined the relation between health literacy and health-related quality of life among cancer patients. A cross-sectional survey was conducted with cancer patients in Wisconsin during 2006-2007. Data on sociodemographics, clinical characteristics, health-related quality of life, and health literacy were obtained from the state's cancer registry and a mailed questionnaire. Regression analyses were used to characterize the association between health-related quality of life and health literacy. The study sample included 1,841 adults, newly diagnosed with lung, breast, colorectal, or prostate cancer in 2004 (response rate = 68%). Health-related quality of life was measured with the Functional Assessment of Cancer Therapy-General. Adjusting for confounders, higher health literacy was associated with greater health-related quality of life (p < .0001). Controlling for covariates, we found significant differences between those in the highest and lowest health literacy categories (p < .0001) and in the physical (p < .0001), functional (p < .0001), emotional (p < .0001), and social (p = .0007) well-being subscales. These associations exceeded the minimally important difference threshold for overall health-related quality of life and functional well-being. Health literacy is positively and independently associated with health-related quality of life among cancer patients. These findings support adoption of health literacy best practices by cancer care systems.