Xeroderma Pigmentosum (XP) is a rare autosomal recessive disorder characterized by an extreme sensitivity to UV rays from sunlight, a high incidence of skin cancer and occasional neurological symptoms. XP, primarily defined as a DNA repair syndrome, has been found associated with defects in the Nucleotide Excision Repair (NER) pathway, and more recently by transcriptional deregulation. XP results from mutations in eight genes (XPA to XPG and XPV) coding for proteins involved in NER. Abstract We report here two cases of XP patients from Algeria, describe their clinical features, identify the causative mutations, and molecularly define their etiology. We determined that each XP individual bears XPC and XPA mutations respectively. Both mutations disrupt expression of their corresponding genes: while the XPC p.Val548Alafs*25 variant was not expressed, the truncated XPA p.Arg228* variant was detected in the patient's cells. Unscheduled DNA synthesis (UDS) and Recovery of RNA synthesis after DNA damage (RRS) assays, as well as immunofluorescence on Ultraviolet-irradiated patient cells showed deficiency in the NER pathway. Moreover, we also found that the patients' cells were defective in transcription, especially certain Retinoic-acid receptor (RAR)-responsive genes. Altogether our data revealed both DNA repair and transcriptional defaults that defined the molecular etiology for these two XP individuals, and may help to understand some of the patients' clinical features.