Surveillance and epidemic modeling were used to study chronic wasting disease (CWD), a transmissible spongiform encephalopathy that occurs naturally among sympatric, free-ranging deer (Odocoileus spp.) and Rocky Mountain elk (Cervus elaphus nelsoni) populations in contiguous portions of northeastern Colorado and southeastern Wyoming (USA). We used clinical case submissions to identify endemic areas, then used immunohistochemistry to detect CWD-infected individuals among 5,513 deer and elk sampled via geographically-focused random surveys. Estimated overall prevalence (prevalence, 95% confidence interval) in mule deer (4.9%, 4.1 to 5.7%) was higher than in white-tailed deer (2.1%, 0.5 to 3.4%) or elk (0.5%, 0.001 to 1%) in endemic areas; CWD was not detected in outlying portions of either state. Within species, CWD prevalence varied widely among biologically- or geographically-segregated subpopulations within the 38,137 km² endemic area but appeared stable over a 3-yr period. The number of clinical CWD cases submitted from an area was a poor predictor of local CWD prevalence, and prevalence was typically ≥1% before clinical cases were first detected in most areas. Under plausible transmission assumptions that mimicked field data, prevalence in epidemic models reached about 1% in 15 to 20 yr and about 15% in 37 to 50 yr. Models forecast population declines once prevalence exceeded about 5%. Both field and model data supported the importance of lateral transmission in CWD dynamics. Based on prevalence, spatial distribution, and modeling, we suggest CWD has been occurring in northeastern Colorado and southeastern Wyoming for >30 yr, and may be best represented as an epizootic with a protracted time-scale.