This research compared the effectiveness of Hantavirus Pulmonary Syndrome (HPS) outreach programs in New Mexico, Panama, and Chile. Understanding the role of human demographics, disease ecology, and human behavior in the disease process is critical to the examination of community responses in terms of behavior changes. Attitudes, knowledge, and behavior across three populations were measured through the implementation of a self-administered questionnaire (N = 601). Surveys implemented in Chile and Panama in 2004, followed by northwestern New Mexico in 2008, attempted to assess knowledge and behavior change with respect to hantavirus in high- and lower-risk prevalence areas during endemic periods. While levels of concern over contracting hantavirus were lowest in New Mexico, they were highest in Panama. Respondents in Chile showed mid-level concern and exhibited a tendency to practice proper cleaning methods more than in New Mexico and Panama. This indicates that public health messages appear to be more effective in Chile. However, since negative behavior changes, such as sweeping and vacuuming, occur at some level in all three populations, improved messages should help decrease risk of exposure to HPS.