Objectives: To evaluate the alteration of protein of programmed cell death 5 (PDCD5) in peripheral blood mononuclear cells (PBMC) and DNA methylation caused by hexavalent chromium exposure. Methods: There were 112 workers and 56 controls in this study. The chromium in RBC and urine, PBMC with PDCD5 + , DNA methylation, urinary 8-hydroxy-2′-deoxyguanosine (8-OHdG) and score of DNA damage were measured. Results: In chromate exposed workers, the percent of PBMC with PDCD5 + , urine 8-OHdG, and score of DNA damage were significantly higher, whereas global DNA methylation was significantly lower. The binary logistic regression and generalized linear mixed model analysis showed that the percent of PBMC with PDCD5 + was significantly associated with global DNA hypomethylation. Conclusions: The aberrant DNA hypomethylation plays an important role in PBMC apoptosis of occupational hexavalent chromium exposure.