Human leptospirosis is an infection that most often affects tropical countries. Since 2007, Colombia requires the notification of disease cases, enabling the observation of an increase in cases in recent years. The objectives of this article were to analyze environmental and socioeconomic variables and to evaluate their relationship with human leptospirosis cases. This is an ecological study on human leptospirosis cases aggregated by municipality and reported between 2007 and 2016. Spatial aggregation assessment was made using the Getis-Ord Gi method, and negative binomial regression was used to evaluate the relationship between environmental and socioeconomic variables with human leptospirosis. During the study period, 9,928 cases of human leptospirosis were reported, and 58.9% of municipalities reported at least one case. Four hotspots of human leptospirosis, including 18 municipalities, were identified. The results of the negative binomial model confirmed the importance of the effects of education, poverty and some climatic variables on the decadal incidence rate of human leptospirosis. Our results confirm the importance of socioeconomic determinants such as social marginality associated with violence and education, as well as ecological variables such as rainfall, height above sea level and forest coverage on the incidence rate of human leptospirosis at municipal scale.