Photochemotherapy using psoralens and UVA radiation (PUVA) is an established treatment for many skin disorders. Psoralen-DNA interactions as well as PUVA-induced reactive oxygen intermediates (ROI) might account for the biologic effects of PUVA. Antiinflammatory and antiproliferative effects of PUVA might be caused by inhibition of replication and/or transcription. We have investigated the effects of single applications of PUVA on both replication or transcription in a promyelocytic (HL60) and a keratinocyte (HaCaT) cell line. Proliferation (measured as H3-thymidine incorporation) was inhibited by PUVA in both cell lines. The inhibition increased with increasing 8-methoxypsoralen (8-MOP) concentrations or UVA dosages and was effective at conditions not affecting cell viability up to 48h after PUVA. Since PUVA induced DNA modifications might not only interfere with replication, but also with transcription at promoter sites, we studied the effect of PUVA on the transcription of ICAM-1 and c-Jun. In HL60 cells, both low constitutive and high IFN-γ induced ICAM-1 mRNA expression was not influenced by PUVA (500 ng/ml of 8-MOP; 0.25 J/cm 2 UVA). Similarly, low constitutive and high phorbol ester induced c-Jun mRNA expression was not inhibited by PUVA. These findings suggest that PUVA causes inhibition of proliferation, but not gene transcription, and that interference with replication may be the primary therapeutic effect of UVA induced psoralen-DNA cross links. In order to assess possible transcriptional effects of PUVA generated ROI, the ROI sensitive transcription factor NFκB was assayed in mobility shift assays. NFκB-specific binding activity was not induced 1 to 24h after PUVA (500 ng/ml of 8-MOP; 1.0 J/cm 2 UVA) in extracts from PUVA treated HaCaT cells when compared to untreated controls, while the pro-oxidant TNF-α did cause a marked increase in NFκB-specific binding after 1h. These data do not support a major role for PUVA generated ROI in transcriptional regulation.