Fatalistic beliefs about cancer are associated with decreased likelihood of knowing about cancer risk factors and engaging in cancer prevention and screening behaviors. Research suggests that Latinas are especially likely to hold fatalistic beliefs. However, this research has been in less-acculturated, high-poverty convenience samples. This study examined cancer knowledge, cancer fatalism, and the association between fatalism and knowledge in a national sample of highly acculturated, middle-income Latinas (N = 715). Results indicate that cancer fatalism is pervasive, and knowledge about cancer risk factors is lacking among this population. Fatalistic beliefs are paradoxically associated with cancer knowledge. Opportunities for tailored communications to improve health behaviors and additional research to understand causes/effects of these findings are discussed in the context of a growing body of research about how to communicate health information to more-acculturated Latinos.