Background/objectives: Major bleeding in patients with acute coronary syndrome (ACS) increases the risk of recurrent ACS and mortality. However, the mechanism involved is poorly understood. Bleeding induces iron deficiency. Iron deficiency enhances inflammation in other diseases. Thus, in this paper, the particular effect of iron deficiency on atherosclerotic plaque destabilization, especially the pro-inflammatory role of iron deficiency in atheroma and the mechanism involved were investigated. Methods: Extracellular matrix metalloproteinase inducer (EMMPRIN) and matrix metalloproteinase-9 (MMP-9) mRNA levels were investigated by RT-PCR. EMMPRIN and MMP-9 protein levels, nuclear factor (NF)-I super(o)B-p65 protein levels, peroxisome proliferator-activated receptor gamma (PPARgamma) protein levels, and mitogen-activated protein kinase (MAPK) phosphorylation were determined by western blotting. MMP-9 enzymatic activity was assayed by gelatin zymography. Results: Iron deficiency enhanced EMMPRIN, MMP-9 production, and MMP-9 enzymatic activity in THP-1 derived macrophages and foam cells. Iron deficiency elicited the activation of NF-I super(o)B and p38 MAPK. By using the p38 inhibitor and NF-I super(o)B inhibitor, the study established that EMMPRIN and MMP-9 inductions by iron deficiency required the consecutive upstream activation of p38 MAPK and NF-I super(o)B. This pro-inflammatory action was not prevented by PPARgamma agonist. Meanwhile, iron deficiency did not modulate PPARgamma expression. Retinoid X receptor agonist suppressed the effects of iron deficiency on EMMPRIN. MMP-9, and NF-I super(o)B, but not on MAPK activation. Conclusions: Iron deficiency enhances atheroma inflammation through p38 MAPK-NF-I super(o)B-EMMPRIN/MMP-9 pathway. Our findings provide a potential mechanism for the association of major bleeding with recurrent ACS and mortality in patients with ACS.