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Protein-protein interactions (PPIs) are involved in most cellular processes. Unfortunately, current knowledge of host-pathogen interactomes is still very limited. Experimental methods used to detect PPIs have several limitations, including increasing complexity and economic cost in large-scale screenings. Hence, computational methods are commonly used to support experimental data, although they generally suffer from high false-positive rates. To address this issue, we have created HPIPred, a host-pathogen PPI prediction tool based on numerical encoding of physicochemical properties. Unlike other available methods, HPIPred integrates phenotypic data to prioritize biologically meaningful results. We used HPIPred to screen the entire Homo sapiens and Pseudomonas aeruginosa PAO1 proteomes to generate a host-pathogen interactome with 763 interactions displaying a highly connected network topology. Our predictive model can be used to prioritize protein–protein interactions as potential targets for antibacterial drug development. Available at: https://github.com/SysBioUAB/hpi_predictor.