MNDA (human myeloid nuclear differentiation antigen) is expressed in specific lineages of hematopoietic cells and most notably at high levels in macrophages at sites of inflammation. MNDA and related proteins appear to modulate the activity of transcription factors and in some cases have a role in mediating cell death. The expression of MNDA was characterized in normal and diseased human aorta. MNDA positive cells double labeled for CD68 in all tissue examined. Twenty percent of normal aortas were negative or contained rare MNDA positive cells while other normal aorta contained more frequent positive cells. In atherosclerotic aorta, the number of MNDA positive cells increased with progression of disease. In normal and early lesions, MNDA positive cells adjacent to the endothelium generally displayed a strong MNDA reactivity associated with small amount of CD68 reactive cytoplasm. In the same sections, MNDA positive cells at increasing distances from the endothelium displayed lower MNDA reactivity and were associated with larger amounts of CD68 reactive cytoplasm. Foam cells in fatty streaks exhibited MNDA reactivity that ranged from strong to weak or negative. In advanced lesions, cells in the shoulder and those in fibrous tissue surrounding an atheroma were highly reactive for MNDA. However, only a fraction of the CD68 positive foam cells near the lipid core under the cap and shoulder contained MNDA reactivity. The variation in MNDA expression appeared to change with phenotypic specialization of monocytes in atherosclerosis consistent with its association with inflammation and suspected roles in regulating gene expression or in mediating cell death.