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OBJECTIVE: To analyze the spread of human American visceral leishmaniasis and identify the key municipalities for developing surveillance and control activities. METHODS: The area of the study was composed of the 316 municipalities in the state of Sao Paulo belonging to the five health districts in which human American visceral leishmaniasis occurs, using data on autochthonous cases and deaths according to the reporting year and municipality in which the death occurred. The incidence, mortality and case fatality rates for each municipality and for the entire area were calculated. An empirical Bayes estimator was used to calculate the local Bayesian incidence and rates of mortality per municipality, and Kriging was used to visualize the spatial distribution of temperature and rainfall. RESULTS: A total of 73 municipalities with transmission of the disease were identified. Human American visceral leishmaniasis was first detected in areas with higher temperatures and lower rainfall, but it also spread in cooler and wetter areas. The expansion of human American visceral leishmaniasis occurred along a main axis of dissemination, from Northwest to Southeast, following the Marechal Rondon highway and the Bolivia-Brazil gas pipeline, and along a secondary axis that was derived from the main axis, which runs both North and South, following the highway network. Rates of incidence according to health district exhibit a peak, followed by a fall, except the Sao Jose do Rio Preto region. Higher concentrations of municipalities with high incidence and mortality rates were observed in the Araçatuba, Presidente Prudente and Marília health districts. CONCLUSIONS: This study indicates possible determinants of the spread of disease, including the Marechal Rondon highway and the construction of the Bolivia-Brazil gas pipeline. Climatic factors seemed to play no role in the spread. The use of spatial analysis techniques allowed the municipalities where cases and deaths are possibly underreported to be identified, which indicated the municipalities which should be prioritized for the development of surveillance and control activities. [ABSTRACT FROM AUTHOR]