Endothelial dysfunction and impaired endothelial regenerative capacity are key contributors to the high incidence of cardiovascular disease in patients with chronic kidney disease (CKD). Uremic toxins are associated with this pathogenesis. Previous studies have revealed that a uremic toxin, para-cresol (p-cresol), exerts an antiproliferation effect on human endothelial progenitor cells (EPCs), but the mechanism remains unclear. In the present study, reactive oxygen species (ROS) were confirmed to function as signaling molecules that regulate growth factor-dependent EPC proliferation. EPCs were treated with p-cresol for 72 h, using a concentration range typically found in CKD patients. ROS production was analyzed by fluorescence microscopy and flow cytometry, and protein expression levels of nicotinamide adenine dinucleotide phosphate oxidase, a major source of ROS, were analyzed by western blot analysis. mRNA expression levels of antioxidant genes were assessed by reverse transcription-quantitative polymerase chain reaction analysis. The results revealed that p-cresol partially inhibits ROS production, and this effect may be associated with a significant reduction in cytochrome b-245 alpha and beta chain expression in EPCs. An increase of glutathione peroxidase 4 mRNA expression was also detected. In conclusion, the present study revealed that the antiproliferation effect of p-cresol on EPCs might act via its antioxidant activity. The results of the present study may facilitate understanding of uremic toxin toxicity on the cardiovascular system.