NHPig is an Innovative Health Initiative (IHI) project based on the public-private partnership of the European Union and Europe’s health industries. Its objective is to expand, share and implement biological knowledge of mini-/micropig models with the aim to reduce non-human primates (NHPs) in non-clinical safety studies. The transnational consortium includes experts in porcine medical models, veterinary pathology, computational animal science, non-clinical science, OMICs profiling, new approach methods (NAMs), as well as bioinformatics and artificial intelligence. NHPig will i) characterise humanised minipigs, micropigs and tailored disease models, including systematic biobanking, multi-OMICs profiling, and state-of-the-art imaging modalities; ii) develop, validate and implement biosensors, medical devices, and ‘intelligent’ animal housing for automated data collection and analysis in minipig safety studies; iii) fill significant knowledge gaps in the (patho)physiology of the porcine immune system; iv) validate known toxicity and efficacy biomarkers and discover novel biomarker candidates for non-clinical safety assessment; v) overcome the shortage of laboratory tools and reagents, such as validated antibodies; vi) gain experience in using mini-/micropigs for safety testing of biologicals and new therapeutic modalities; vii) Investigate in vitro to in vivo extrapolation of liver and kidney toxicity in pigs and NHP/humans to provide a comparative link to human new approach methodologies (NAMs); and viii) provide a publicly available database and IT platform for compiling, integrating and analysing existing data in NHPs/humans with data in mini-/micropig models (existing data and data generated within the NHPig programme). The establishment of a regulatory advisory board and an ethics- and animal welfare advisory board will expedite regulatory interactions and ensure compliance with the 3R principles. NHPig will generate the scientific basis for de-selection of NHPs in non-clinical safety assessment, which is an ethical requirement and also imperative according to EU legislation.