A long-term monitoring program begun 1 year after the epidemic of hantavirus pulmonary syndrome in the U.S. Southwest tracked rodent density changes through time and among sites and related these changes to hantavirus infection rates in various small-mammal reservoir species and human disease outbreaks. We assessed the statistical sensitivity of the program's field design and tested for potential biases in population estimates due to unintended deaths of rodents. Analyzing data from two sites in New Mexico from 1994 to 1998, we found that for many species of Peromyscus, Reithrodontomys, Neotoma, Dipodomys, and Perognathus, the monitoring program detected species-specific spatial and temporal differences in rodent densities; trap-related deaths did not significantly affect long-term population estimates. The program also detected a short-term increase in rodent densities in the winter of 1997-98, demonstrating its usefulness in identifying conditions conducive to increased risk for human disease.