<p>Members of the U.S. public report negative stereotypes, prejudice, and discrimination towards individuals with a variety of health issues. The present study aimed to identify which health conditions and behaviors are most stigmatized and shed light on the factors that drive variation in stigma. A large, nationally representative sample of U.S. adults (<i>N</i> = 1,096) provided valid online survey responses to the Relative Understanding of Stigma about Health Index (RUSH-I), a novel instrument that assesses perceptions of controllability, knowledge, and perceptions of public stigma for 36 different conditions and behaviors. We hypothesized a positive relationship between controllability and stigma and an inverse relationship between knowledge and stigma. As hypothesized, stigma was substantially higher among conditions and behaviors that participants perceived as more controllable and about which they reported less knowledge. Controllability and knowledge accounted for over two-thirds of the variance in stigma across health issues. At the individual level, however, knowledge was <i>positively</i> related to stigma: Participants who reported more knowledge about a health condition or behavior tended to perceive greater stigma associated with it. Results showed that mental health conditions were generally more stigmatized than physical health conditions. Obesity was a notable exception, ranking as the most stigmatized health condition overall. These findings may help guide public health messaging, especially which conditions should be targets for stigma intervention. The findings also highlight important areas for further research, including elaborating the relationship between knowledge and stigma at both the individual and condition level.</p>