The Mediterranean (MED) diet is often considered health-promoting due to its high content of MUFA and polyphenols. These bioactive compounds can affect gene expression and accordingly may regulate pathways and proteins related to cardiovascular disease prevention. This study aimed to identify the effects of a MED-type diet, and the replacement of SFA with MUFA in a Western-type diet, on peripheral blood mononuclear cell (PBMC) gene expression and plasma proteins. Abdominally overweight men and women (waist: women ≥80cm, men ≥94cm) were allocated to an 8-wk, completely controlled SFA diet (19% daily energy as SFA), a MUFA diet (20% daily energy MUFA), or a MED diet (21% daily energy MUFA). Concentrations of 124 plasma proteins and PBMC whole-genome transcriptional profiles were assessed. Consumption of the MUFA and MED diets, compared with the SFA diet, decreased the expression of oxidative phosphorylation (OXPHOS) genes, plasma connective tissue growth factor, and apoB concentrations. Compared with the MED and SFA diets, the MUFA diet changed the expression of genes involved in B-cell receptor signaling and endocytosis signaling. Participants who consumed the MED diet had lower concentrations of proinflammatory proteins at 8 wk compared with baseline. We hypothesize that replacement of SFA with MUFA may improve health, thereby reducing metabolic stress and OXPHOS activity in PBMC. The MED diet may have additional antiatherogenic effects by lowering proinflammatory plasma proteins.