To investigate the late and persistent effects of cadmium (Cd) at low doses on the liver and its potential mechanisms, male Wistar rats were given i.p. injection of Cd as CdCl2 at 20 nmol kg−1 body weight every other day for 4 weeks. At weeks 20, 44 and 52, the livers from Cd-treated and age-matched control rats were examined pathologically and biochemically. Chronic exposure of rats to Cd at low doses induced mild pathological changes and persistent oxidative damage as well as cell proliferation. Hepatic proteins were analyzed with two-dimensional electrophoresis (2-DE) and mass spectrometry. More than 1000 protein spots were detected by 2-DE. Ten proteins were distinguishable between Cd-treated and age-matched control groups at week 52 week after Cd treatment. Two of them were significantly down-regulated: prohibitin (PHB) and d-dopachrome tautomerase (DDT). By western blotting the down-regulated expression of PHB and DDT in the livers of Cd-treated rats was confirmed in both early (week 20) and late (week 52) time points. To further examine the down-regulation of antioxidant status in the Cd-treated livers, other common antioxidants, including superoxide dismutase and glutathione and one metal detoxification specific protein metallothionein, were also detected and found to be decreased, particularly at the late stage. These results suggest that mild histopathological changes, persistent oxidative damage and cell proliferation remained at the late stages (weeks 44–52) after rats were exposed to low-dose Cd. These persistent changes may be associated with the persistent down-regulation of cellular antioxidant systems. Copyright © 2011 John Wiley & Sons, Ltd.