Hantavirus cardiopulmonary syndrome (HCPS), a rodent-borne zoonosis, has been endemic in the Americas for at least several decades. It is hypothesized that the 1991-1992 El Niño-southern oscillation (ENSO) caused increased precipitation that allowed an increase in rodent population densities, thereby increasing the possibility of transmission to humans. The result was a 1993-1994 outbreak of the disease in the Four Corners states of the southwestern United States. A second strong ENSO occurred in 1997-1998, after a period of considerable public education about the risks of hantavirus infection that began during the 1993-1994 outbreak. The caseload of HCPS increased 5-fold above baseline in the Four Corners states in 1998-1999. Regions that had received increased rainfall in 1998 were especially affected. A large majority of the 1998-1999 case patients reported indoor exposure to deer mice. Hantavirus outbreaks can occur in response to abiotic events, even in the face of extensive public education and awareness.