Multiple linear regression models were fitted to look for associations between changes in the incidence rate of dengue fever and climate variability in the warm and humid region of Mexico. Data were collected for 12 Mexican provinces over a 23-year period (January 1985 to December 2007). Our results show that the incidence rate or risk of infection is higher during El Niño events and in the warm and wet season. We provide evidence to show that dengue fever incidence was positively associated with the strength of El Niño and the minimum temperature, especially during the cool and dry season. Our study complements the understanding of dengue fever dynamics in the region and may be useful for the development of early warning systems.