This paper introduces and applies a novel methodology that integrates watershed modeling with the traditional regional flood frequency analysis. The methodology introduces a novel site-similarity measure that relies on hydrologic simulations and accounts for the effect of land depressions on streamflow generation. The new measure is tested along with other traditional measures for regional flood frequency analysis in the Canadian prairies. The case study is chosen carefully to critically test the new methodology. An application of 30 combinations of the new and traditional site similarity measures is assessed for pooling 109 sites. The homogeneity of the clustered groups is evaluated, and different probability distributions are applied to describe at-site and regional annual maximum flows. The results present enhanced groups’ homogeneity when the new measure is employed due to a better representation of the hydrologic similarity between the pooled sites. Furthermore, the regionally estimated quantiles are found susceptible to the chosen site similarity measures in the pooling process, which highlights the importance of considering the proposed measure that describes a key hydrologic aspect when land depressions exist