Water-soluble and particulate cadmium compounds are carcinogenic to humans. While direct interactions with DNA are unlikely to account for carcinogenicity, induction of oxidative DNA damage and interference with DNA repair processes might be more relevant underlying modes of action (recently summarized, for example, in Joseph , P. (2009) Tox. Appl. Pharmacol. 238 , 271 - 279). The present study aimed to compare genotoxic effects of particulate CdO and soluble CdCl(2) in cultured human cells (A549, VH10hTert). Both cadmium compounds increased the baseline level of oxidative DNA damage. Even more pronounced, both cadmium compounds inhibited the nucleotide excision repair (NER) of BPDE-induced bulky DNA adducts and UVC-induced photolesions in a dose-dependent manner at noncytotoxic concentrations. Thereby, the uptake of cadmium in the nuclei strongly correlated with the repair inhibition of bulky DNA adducts, indicating that independent of the cadmium compound applied Cd(2+) is the common species responsible for the observed repair inhibition. Regarding the underlying molecular mechanisms in human cells, CdCl(2) (as shown before by Meplan, C., Mann, K. and Hainaut, P. (1999) J. Biol. Chem. 274 , 31663 - 31670 ) and CdO altered the conformation of the zinc binding domain of the tumor suppressor protein p53. In further studies applying only CdCl(2), cadmium decreased the total nuclear protein level of 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, CdCl(2) strongly disturbed the disassembly of XPC and XPA. In summary, our data indicate a general nucleotide excision repair inhibition by cadmium compounds, which is most likely caused by a diminished assembly and disassembly of the NER machinery. These data reveal new insights into the mechanisms involved in cadmium carcinogenesis and provide further evidence that DNA repair inhibition may be one predominant mechanism in cadmium induced carcinogenicity.