BACKGROUND: Mathematical models of human mobility have demonstrated a great potential for infectious disease epidemiology in contexts of data scarcity. While the commonly used gravity model involves parameter tuning and is thus difficult to implement without reference data, the more recent radiation model based on population densities is parameter-free, but biased. In this study we introduce the new impedance model, by analogy with electricity. Previous research has compared models on the basis of a few specific available spatial patterns. In this study, we use a systematic simulation-based approach to assess the performances. METHODS: Five hundred spatial patterns were generated using various area sizes and location coordinates. Model performances were evaluated based on these patterns. For simulated data, comparison measures were average root mean square error (aRMSE) and bias criteria. Modeling of the 2010 Haiti cholera epidemic with a basic susceptible-infected-recovered (SIR) framework allowed an empirical evaluation through assessing the goodness-of-fit of the observed epidemic curve. RESULTS: The new, parameter-free impedance model outperformed previous models on simulated data according to average aRMSE and bias criteria. The impedance model achieved better performances with heterogeneous population densities and small destination populations. As a proof of concept, the basic compartmental SIR framework was used to confirm the results obtained with the impedance model in predicting the spread of cholera in Haiti in 2010. CONCLUSIONS: The proposed new impedance model provides accurate estimations of human mobility, especially when the population distribution is highly heterogeneous. This model can therefore help to achieve more accurate predictions of disease spread in the context of an epidemic.