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Many hydrologic applications require reliable estimates of runoff in river basins to face the widespread lack of data, both in time and in space. A regional method for the reconstruction of monthly runoff series is here developed and applied to Sicily (Italy). A simple modeling structure is adopted, consisting of a regression-based rainfall-runoff model with four model parameters, calibrated through a two-step procedure. Monthly runoff estimates are based on precipitation, temperature, and exploiting the autocorrelation with runoff at the previous month. Model parameters are assessed by specific regional equations as a function of easily measurable physical and climate basin descriptors. The first calibration step is aimed at the identification of a set of parameters optimizing model performances at the level of single basin. Such optimal sets are used at the second step, part of a regional regression analysis, to establish the regional equations for model parameters assessment as a function of basin attributes. All the gauged watersheds across the region have been analyzed, selecting 53 basins for model calibration and using the other six basins exclusively for validation. Performances, quantitatively evaluated by different statistical indexes, demonstrate relevant model ability in reproducing the observed hydrological time-series at both the monthly and coarser time resolutions. The methodology, which is easily transferable to other arid and semi-arid areas, provides a reliable tool for filling/reconstructing runoff time series at any gauged or ungauged basin of a region.