Treatment of cells with psoralen and ultraviolet A light (UVA) modulates their cytokine production. As extracorporeal photochemotherapy has been reported to induce cytokine production by monocytes, we quantified interleukin-8 (IL-8), a representative chemokine produced by monocytes, in culture supernatants from human peripheral blood mononuclear cells (PBMC) treated with 8-methoxypsoralen (8-MOP) and UVA. Lipopolysaccharide stimulated IL-8 production in 8-MOP-phototreated PBMC more efficiently than those untreated or treated with 8-MOP or UVA. More interestingly, when cultured with T-cell-stimulating anti-CD3 and anti-CD28 antibodies, 8-MOP/UVA-treated PBMC produced enhanced amounts of IL-8 with an increased level of IL-8 mRNA expression. Depletion of CD4 but not CD8 T cells from PBMC abrogated this augmented IL-8 elaboration, and CD4 T cells per se secreted no substantial amount of IL-8 even upon CD3/CD28 stimulation. Thus, 8-MOP/UVA-treated CD4 T cells stimulated monocytes to secrete IL-8. The IL-8 overproduction was induced by direct contact of monocytes with 8-MOP/UVA-treated CD4 T cells but not by cytokines from the treated CD4 T cells. These findings imply that in extracorporeal photochemotherapy, monocytes effectively produce IL-8 by cell-to-cell contact with 8-MOP/UVA-treated malignant CD4 T cells. The augmentation of monocyte cytokine/chemokine production by 8-MOP/UVA may be one of the mechanisms underlying the therapeutic efficacy of extracorporeal photochemotherapy.