Chronic wasting disease (CWD), a transmissible spongiform encephalopathy that affects white-tailed deer (Odocoileus virginianus) and other cervids, is increasing in geographic distribution and prevalence and causing population declines. To mitigate CWD spread, wildlife management agencies frequently allow hunters to harvest more deer (i.e., CWD management zones) and remove symptomatic or asymptomatic deer from locations where CWD has been detected (i.e., post-harvest targeted culling). However, it is unclear how factors such as geographic location of CWD introduction, age and sex of deer that introduce CWD, geographic location and extent of CWD management zones, harvest within CWD management zones, and post-harvest targeted culling may affect the establishment and spread of CWD in a region. By simulating a CWD outbreak using the OvCWD modeling framework, we explored how such factors impact effectiveness of CWD management in northwest Indiana and northeast Illinois, USA. Location of CWD introduction and age-sex class of the deer introducing CWD had the largest effect on geographic spread of CWD and fadeout probability. Larger CWD management zones (2,352 km2) increased fadeout probability and decreased geographic spread more than smaller zones (976 km2 or 532 km2). Increasing harvest by ≥200% within the largest management zone, especially in combination with post-harvest culling, also resulted in greater fadeout probability and reduced spread. Fadeout probability increased and geographic spread decreased with increasing percentage of deer tested for CWD and percentage of deer removed during culling. The location of disease introduction and demographics of the deer that introduce disease proved important when simulating CWD outbreaks using agent-based models. Our simulations demonstrate that increases in harvest and culling must be greater than those currently in practice to slow the spread of CWD. Although control of CWD using the strategies simulated may be epidemiologically possible, such management may be intractable given current levels of deer hunter participation and desire to harvest more deer. These findings provide decision makers with information needed to determine the feasibility of CWD management strategies.