There is considerable evidence to suggest that cytokines modulate the pathological cellular events that occur in human atherosclerosis. We sought to determine the effects of T-helper-lymphocyte (T_H)-1- and T_H2-type cytokines on the ability of human monocytes to oxidize LDL, one of the pathological processes believed to occur in atherosclerosis. The ability of opsonized zymosan (ZOP)-activated human monocytes to oxidize LDL in a 24-hour period was significantly enhanced by pretreatment of the monocytes with the T_H2 cytokines, interleukin (IL)-4, or IL-13 compared with untreated monocytes. In contrast, interferon (IFN)-γ, a T_H1 cytokine, inhibited LDL oxidation by activated monocytes. Treatment with IFN-γ also prevented the IL-4- and IL-13-mediated enhancement of LDL oxidation by ZOP-activated monocytes. Untreated or cytokine-treated unactivated monocytes did not oxidize LDL. The enhancement of LDL oxidation mediated by IL-4 or IL-13 treatment was not due to a mitogenic effect of the cytokines on the monocytes, nor to modulation of superoxide anion (O₂⁻) production. The cytokine regulation of 15-lipoxygenase (LO) in the monocytes was also examined. IL-4 and IL-13 induction of 15-LO mRNA and 15-LO activity in the monocytes was confirmed, as was the previously reported inhibition of induction by IFN-γ. In summary, IL-4 and IL-13 enhance the ability of activated human monocytes to oxidize LDL, whereas IFN-γ inhibits the cell-mediated oxidation. The up- and downregulation of activated monocyte-mediated LDL oxidation by these cytokines correlates with the expression of 15-LO activity. Considerable evidence suggests that the progression of atherosclerosis includes events that are immunologically mediated, lending potential physiological relevance to these in vitro observations.