Severe asthma represents an important clinical unmet need despite the introduction of biologic agents. Although advanced omics technologies have aided researchers in identifying clinically relevant molecular pathways, there is lack of integrated omics approach in severe asthma particularly in terms of its evolution over time. The collaborative Korea-UK research project, Precision Medicine Intervention in Severe Asthma (PRISM), was launched in 2020 with the aim of identifying molecular phenotypes of severe asthma by analyzing multi-omics data encompassing genomics, epigenomics, transcriptomics, proteomics, metagenomics, and metabolomics. PRISM is a prospective, observational, and multicenter study involving patients with severe asthma attending severe asthma clinics in Korea and the UK. Data including patient demographics, inflammatory phenotype, medication, lung function, and control status of asthma will be collected along with biological samples (blood, sputum, urine, nasal epithelial cells, and exhaled breath condensate) for omics analyses. Follow-up evaluations will be performed at baseline, 1 month, 4–6 months, and 10–12 months to assess the stability of phenotype and treatment responses for those patients who have newly begun biologic therapy. Standalone and integrated omics data will be generated from the patient samples at each visit, paired with clinical information. By analyzing these data, we will identify the molecular pathways that drive lung function, asthma control status, acute exacerbations, and the requirement for daily oral corticosteroids and that are involved in the therapeutic response to biological therapy. PRISM will establish a large multi-omics dataset of severe asthma to identify potential key pathophysiological pathways of severe asthma.