BACKGROUND: The aim of this study was to spatially model the effect of demographic, reservoir hosts and environmental factors on human Schistosoma japonicum infection prevalence in the Dongting Lake area of Hunan Province, China and to determine the potential of each indicator in targeting schistosomiasis control. METHODOLOGY/PRINCIPAL FINDINGS: Cross-sectional serological, coprological and demographic data were obtained from the 2004 nationwide periodic epidemiologic survey for Hunan Province. Environmental data were downloaded from the USGS EROS data centre. Bayesian geostatistical models were employed for spatial analysis of the infection prevalence among study participants. A total of 47,139 participants from 47 administrative villages were selected. Age, sex and occupation of residents and the presence of infected buffaloes and environmental factors, i.e. NDVI, distance to the lake and endemic type of setting, were significantly associated with S. japonicum infection prevalence. After taking into account spatial correlation, however, only demographic factors (age, sex and occupation) and the presence of infected buffaloes remained significant indicators. CONCLUSIONS/SIGNIFICANCE: Long established demographic factors, as well presence of host reservoirs rather than environmental factors are driving human transmission. Findings of this work can be used for epidemiologic surveillance and for the future planning of interventions in the Dongting Lake area of Hunan Province.