The design of large-scale wildlife monitoring programs must include long term and geographically broad methods of collecting reliable information on the status and trends in populations, with the overarching goal of providing inference about ecosystem health. We developed a monitoring protocol for populations of beaver (Castor canadensis), American mink (Neovison vison), muskrat (Ondatra zibethicus), and North American river otter (Lontra canadensis) in Illinois, USA. The goals of the monitoring program are to (1) determine the distribution, status and trends of riparian-associated mammal species in Illinois; (2) provide early warning of population declines; (3) contribute to baseline information and improve understanding of ecosystem dynamics; (4) produce data to meet certain legal mandates related to natural resource protection; and (5) measure progress towards wildlife management goals. We developed the riparian-associated mammal protocol in an occupancy modeling framework and provide estimates regarding 2 levels of precision. The estimated number of sites required to meet benchmark precision values was consistently 4 times greater for management objectives requiring more certainty. As estimated occupancy and detection probability increased, estimates of the number of sites necessary to achieve the desired precision decreased. Based on our analysis, goals, and logistical constraints of the Illinois Department of Natural Resources, monitoring 193 sites selected from Illinois Environmental Protection Agency river and stream monitoring sites for riparian-associated mammals is the most appropriate goal. The scientifically sound information obtained through this monitoring program will have multiple applications for wildlife management and understanding of riparian ecosystem dynamics.