The aim of the study was to investigate the influence of chronic fluorosis on apoptosis and the expression of Bax and Bcl-2 in the cerebral cortices of rats in an attempt to elucidate molecular mechanisms. Sixty Sprague Dawley (SD) rats were divided randomly into three groups of 20 each: an untreated control group (drinking water naturally containing <0.5 mg fluoride/L), a low-fluoride (F) group (whose drinking water was supplemented with 10 mg F/L by using NaF) and a high-F group (50 mg F/L). The percentage of apoptotic neurons was detected by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay, after 6 months of exposure. Moreover, the expressions of Bax and Bcl-2 at both the protein and mRNA levels were detected by Western blotting and real-time PCR, respectively. The results showed that the animal model of chronic fluorosis was successfully established in the study. In the cortices of the rat brains with chronic fluorosis, as compared to controls, the percentage of apoptotic neurons was significantly increased, with a dose-dependent tendency between the rate of apoptosis and the F contents in drinking water. The expression of Bax and Bcl-2, at both the protein and mRNA levels, was clearly elevated in the rat brains with chronic fluorosis. These findings indicate that the raised level of apoptosis in cortical neurons resulting from chronic fluorosis may be regulated by Bax and Bcl-2.