Abstract Background The molecular aetiology of inflammatory bowel disease IBD and its two subtypes, ulcerative colitis UC and Crohn’s disease CD, have been carefully investigated at genome and transcriptome levels. Recent advances in high-throughput proteome quantification has enabled comprehensive large-scale plasma proteomics studies of IBD. Methods The study used two cohorts: 1 The CERTIFI-cohort: 42 samples from the CERTIFI trial of anti-TNFα–refractory CD patients; 2 the PROgECT-UNITI-HCs cohort: 46 UC samples of the PROgECT study, 84 CD samples of the UNITI I and UNITI II studies, and 72 healthy controls recruited in Mount Sinai Hospital, New York, USA. The plasma proteome for these two cohorts was quantified using high-throughput platforms. Results For the PROgECT-UNITI-HCs cohort, we measured a total of 1310 proteins. Of these, 493 proteins showed different plasma levels in IBD patients to the plasma levels in controls at 10% false discovery rate FDR, among which 11 proteins had a fold change greater than 2. The proteins upregulated in IBD were associated with immunity functionality, whereas the proteins downregulated in IBD were associated with nutrition and metabolism. The proteomic profiles were very similar between UC and CD. In the CERTIFI cohort, 1014 proteins were measured, and it was found that the plasma protein level had little correlation with the blood or intestine transcriptomes. Conclusions We report the largest proteomics study to date on IBD and controls. A large proportion of plasma proteins are altered in IBD, which provides insights into the disease aetiology and indicates a potential for biomarker discovery.