Chronic wasting disease (CWD) is an invariably fatal transmissible spongiform encephalopathy of white-tailed deer, mule deer, elk, and moose. Despite a 100% fatality rate, areas of high prevalence, and increasingly expanding geographic endemic areas, little is known about the population-level effects of CWD in deer. To investigate these effects, we tested the null hypothesis that high prevalence CWD did not negatively impact white-tailed deer population sustainability. The specific objectives of the study were to monitor CWD-positive and CWD-negative white-tailed deer in a high-prevalence CWD area longitudinally via radio-telemetry and global positioning system (GPS) collars. For the two populations, we determined the following: a) demographic and disease indices, b) annual survival, and c) finite rate of population growth (λ). The CWD prevalence was higher in females (42%) than males (28.8%) and hunter harvest and clinical CWD were the most frequent causes of mortality, with CWD-positive deer over-represented in harvest and total mortalities. Survival was significantly lower for CWD-positive deer and separately by sex; CWD-positive deer were 4.5 times more likely to die annually than CWD-negative deer while bucks were 1.7 times more likely to die than does. Population λ was 0.896 (0.859–0.980), which indicated a 10.4% annual decline. We show that a chronic disease that becomes endemic in wildlife populations has the potential to be population-limiting and the strong population-level effects of CWD suggest affected populations are not sustainable at high disease prevalence under current harvest levels.