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Scope. To explore the effect of a healthy Nordic diet on the global transcriptome profile in peripheral blood mononuclear cells (PBMCs) of subjects with metabolic syndrome. Methods and results. Subjects with metabolic syndrome undergo a 18/24 week randomized intervention study comparing an isocaloric healthy Nordic diet with an average habitual Nordic diet served as control (SYSDIET study). Altogether, 68 participants are included. PBMCs are obtained before and after intervention and total RNA is subjected to global transcriptome analysis. 1302 probe sets are differentially expressed between the diet groups (p‐value < 0.05). Twenty‐five of these are significantly regulated (FDR q‐value < 0.25) and are mainly involved in mitochondrial function, cell growth, and cell adhesion. The list of 1302 regulated probe sets is subjected to functional analyses. Pathways and processes involved in the mitochondrial electron transport chain, immune response, and cell cycle are downregulated in the healthy Nordic diet group. In addition, gene transcripts with common motifs for 42 transcription factors, including NFR1, NFR2, and NF‐κB, are downregulated in the healthy Nordic diet group. Conclusion. These results suggest that benefits of a healthy diet may be mediated by improved mitochondrial function and reduced inflammation. The project was funded by NordForsk Nordic Centre of Excellencein Food, Nutrition and Health project 070014 (SYSDIET [Systems Biologyin Controlled Dietary Interventions and Cohort Studies]) and further, OsloMetropolitan University-OsloMet (Norway), University of Oslo (Norway),Throne Holst Foundation (Norway), Academy of Finland, SwedishResearch Council, Svenska Diabetesf ̈orbundet, SRP Diabetes, FinnishDiabetes Research Foundation, Finnish Foundation for CardiovascularResearch, the Sigrid Juselius Foundation, EVO funding from KuopioUniversity Hospital (Finland), the Druvan Foundation, Sk ̊ane UniversityHospital, the Heart-Lung Foundation, Diabetesfonden and FoundationCerealia (Sweden), the Danish Obesity Research Centre (DanORC,www.danorc.dk), the Danish Council for Strategic Research (DairyHealth,BioFunCarb) (Denmark), the Agricultural Productivity Fund, and theResearch Fund of the University of Iceland (Iceland).