DNA is often damaged by many environmental agents, which lead to the up-regulation of several genes involved in different repair pathways. Schistosoma mansoni has a complex life cycle, being exposed to a subset of DNA-damaging agents, such as those present in the environment and host immune response. Recently, studies showed that nucleotide excision repair (NER) is an indispensable mechanism for removing a broad spectrum of different DNA lesions. In the present report, we showed the gene expression of nucleotide excision repair factor 2 (NEF2) SmRad23 and SmRad4, in different developmental stages of S. mansoni, as well as the differential expression of these genes in S. mansoni adult worms treated with DNA-damaging agents. Furthermore, it was revealed the correlation of these genes with their orthologues in other eukaryotes. Our reports suggest that NER is an important repair pathway during the complex life cycle of S. mansoni.