Photochemotherapy using psoralens and UVA radiation is an established treatment for a variety of skin disorders. The exact molecular mechanisms responsible for the antiinflammatory and antiproliferative effects of PUVA are still unknown. Psoralen-DNA interactions as well as modifications of DNA and other intracellular components via reactive oxygen intermediates might play important roles. We have looked at the effects of single applications of PUVA in a promyelocytic (HL60) and a keratinocyte cell line (HaCaT). Proliferation (measured as incorporation of tritiated thymidine) was inhibited by PUVA in both cell lines. This inhibition increased with increasing 8-methoxypsoralen (8-MOP) concentrations or UVA dosages. 8-MOP or UVA alone were not effective. 500 ng/ml of 8-MOP and 0.25 J/cm 2 UVA inhibited HL60 proliferative activity by 85%. These conditions did not affect cell viability until 48 h after PUVA. Since PUVA induced DNA modifications might not only inhibit DNA replication, but also interfere with gene transcription at promoter sites, we studied the effect of PUVA on the expression of ICAM-1, a primarily transcriptionally regulated, immunologically relevant adhesion molecule. Both low constitutive and high IFN-γ induced ICAM-1 mRNA expression was not influenced by 500 ng/ml of 8-MOP and 0.25 J/cm 2 UVA in HL60 cells. In addition, PUVA did not influence constitutive or IFN-γ induced ICAM-1 cell surface expression in HL60 and HaCaT cells over a wide range of 8-MOP concentrations and UVA dosages, even when PUVA was repeated 3 times in some experiments. These data suggest that PUVA causes inhibition of proliferation, but not of gene transcription at sublethal conditions and that interference with DNA replication may be the primary therapeutic effect of UVA induced psoralen-DNA cross links.