This ecological study analyzed the temporal pattern of clinically diagnosed and laboratory confirmed dengue cases in Belo Horizonte, Minas Gerais, Brazil from 1996 to 2017. The study was divided into two analytical parts, the first of which evaluated the association between dengue incidence and host and climatic factors. The second part encompassed data from 2002 to 2017 and examined dengue incidence in relation to virus serotype and an intra-urban socioeconomic index. Over 22 years there were 469,171 cases and four epidemic peaks. There was an increase in the number, severity, and lethality of cases over the last 10 years of the study period. Biological and environmental factors appear to modulate the behavior of dengue in a large urban center.