Treatment with 8-methoxypsoralen (8-MOP) and ultraviolet A light (UVA) has been reported to modulate cytokine production in various cells. Our study was conducted to see the effects of 8-MOP/UVA on the expression/production of cytokines in peripheral blood lymphocytes and monocytes in relation to the therapeutic mechanisms of extracorporeal photochemotherapy. 8-MOP/UVA augmented the expression of mRNAs for interferon-gamma (IFN-gamma) and interleukin (IL)-2 and reduced those for IL-4 and IL-10 in peripheral blood mononuclear cells (PBMCs) from normal subjects and Sézary syndrome patients. This enhancement of Th1 cytokines was caused by increment of cytokine production by Th1 cells but not by conversion of Th2 cells to produce Th1 cytokines. The number of IFN-gamma-secreting lymphocytes was markedly increased in 8-MOP/UVA-treated PBMCs 20 h after treatment, and its amount was elevated in culture supernatants. However, this enhanced production of IFN-gamma was found only until three days after 8-MOP phototreatment, and its level was rapidly declined by five days after treatment. In addition to this Th1-polarized action, 8-MOP/UVA-treated PBMCs produced enhanced amounts of IL-8 upon stimulation with anti-CD3/CD28 antibodies. Phototreated CD4+ but not CD8+ cells provided excellent T cell help for monocytes to produce IL-8 via a direct cell-to-cell contact mechanism. These findings suggest that 8-MOP/UVA has a transient but biologically active Th1-skewing action in T cells, and the phototreated T cells simultaneously stimulate monocytes to produce IL-8. It is suggested that 8-MOP/UVA exerts a beneficial therapeutic effect on malignant Th2 neoplasms as a Th1-skewing cytokine modifier and that 8-MOP-phototreated CD4+ T cells allow monocytes to become effective tumor antigen-presenting cells for tumor-specific cytotoxic T cells.