This study aimed to identify the effects of replacement of saturated fat (SFA) by monunsaturated fat (MUFA) in a western-type diet and the effects of a full Mediterranean (MED) diet on whole genome PBMC gene expression and plasma protein profiles. Abdominally overweight subjects were randomized to a 8 wk completely controlled SFA-rich diet, a SFA-by-MUFA-replaced diet (MUFA diet) or a MED diet. Concentrations of 124 plasma proteins and PBMCs whole genome transcriptional profiles were assessed. Consumption of the MUFA and MED diet, compared with the SFA diet, decreased expression of oxidative phosphorylation (OXPHOS) genes, serum lipids and plasma Connective Tissue Growth Factor, myoglobin and Apo B concentrations. The MED diet additional lowered plasma α-2-macroglobulin concentration compared with the SFA diet. Within the MED diet group concentrations of several pro-inflammatory proteins were lowered. We conclude that MUFA as replacement of SFA in a western-type diet or in a MED diet had similar effects on lowering expression of OXPHOS genes. We hypothesize that replacement of SFA by MUFA increased metabolic health as reflected by lowered serum lipids and certain plasma proteins, thereby reducing metabolic stress and OXPHOS activity in PBMCs. The MED diet may have additional anti-atherogenic effects by lowering concentrations of pro-inflammatory plasma proteins.