Cadmium (Cd) is a toxic heavy metal known to exert severe nephrotoxic effects. Mechanistically, Cd has been reported to disrupt gene expression in renal proximal tubular cells. In addition, alterations in DNA integrity have been reported to be associated with Cd toxicity. Histone proteins play important roles in maintaining DNA integrity, and are responsible for regulating gene transcription. In this study, we examined the involvement of HIST1H4C, a gene encoding the histone H4 protein, in Cd toxicity in HK-2 human proximal tubular cells. It was found that Cd significantly reduced the transcription level of HIST1H4C in HK-2 cells. In addition, HIST1H4C knockdown by siRNA transfection enhanced Cd toxicity in HK-2 cells. Our findings suggest that suppression of gene expression of HIST1H4C may be involved in the elevation of Cd toxicity in proximal tubular cells.