The ubiquitous occurrence of the human carcinogen arsenic results in multiple exposure possibilities to humans. The human diet, especially drinking water, is the primary source of inorganic arsenic intake in the general population. The ingested arsenic is metabolized to methylated derivatives; some of these metabolites are today considered to be more toxic than the inorganic species. Various modes of action have been proposed to contribute to arsenic carcinogenicity; inhibition of nucleotide excision repair (NER), removing DNA helix distorting DNA adducts induced by environmental mutagens, is likely to be of primary importance. Here, we report that arsenite and its metabolite monomethylarsonous acid (MMA(III)) strongly decreased expression and protein level of Xeroderma pigmentosum complementation group C (XPC), which is believed to be the principle initiator of global genome NER. This led to diminished association of XPC to sites of local UVC damage, resulting in decreased recruitment of further NER proteins. Additionally Xeroderma pigmentosum complementation group E protein (XPE) expression was reduced, which encodes for another important NER protein and similarly to XPC is regulated by the activity of the transcription factor p53. In summary, our data demonstrate that in human skin fibroblasts arsenite and even more pronounced MMA(III) interact with XPC expression, resulting in decreased XPC protein level and diminished assembly of the NER machinery.