Climate change and variability are affecting human health and disease direct or indirectly through many mechanisms. Dengue is one of those diseases that is strongly influenced by climate variability; however its study in Central America has been poorly approached. In this study, we assessed potential associations between macroclimatic and microclimatic variation and dengue hemorrhagic fever (DHF) cases in the main hospital of Honduras during 2010. In this year, 3,353 cases of DHF were reported in the Hospital Escuela, Tegucigalpa. Climatic periods marked a difference of 158% in the mean incidence of cases, from El Niño weeks (-99% of cases below the mean incidence) to La Niña months (+59% of cases above it) (p<0.01). Linear regression showed significantly higher dengue incidence with lower values of Oceanic Niño Index (p=0.0097), higher rain probability (p=0.0149), accumulated rain (p=0.0443) and higher relative humidity (p=0.0292). At a multiple linear regression model using those variables, ONI values shown to be the most important and significant factor found to be associated with the monthly occurrence of DHF cases (r2=0.649; βstandardized=–0.836; p=0.01). As has been shown herein, climate variability is an important element influencing the dengue epidemiology in Honduras. However, it is necessary to extend these studies in this and other countries in the Central America region, because these models can be applied for surveillance as well as for prediction of dengue.