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Transforming growth factor-beta2 (TGF-β2) induces anterior subcapsular cataracts, with a marked increase in cytoskeletal and extracellular matrix proteins, such as alpha-smooth muscle actin (αSMA). It has been shown that 17beta-estradiol (E2) can prevent TGF-β2-induced cataracts in lenses from ovariectomized female rats. The purpose of the current study was to extend this finding by testing whether E2 can prevent TGF-β2-induced cataracts and inhibit the induction of αSMA gene expression in normal male and normal, non-ovariectomized female rats.Sex-specific differences were observed in 17-week-old rat lenses incubated in 0·15 ng ml−1 TGF-β2 and in 10−8 M E2 plus TGF-β2. TGF-β2 induced approximately twice as many anterior subcapsular plaques and 1·5 times the level of αSMA transcripts in male lenses compared to female lenses. Notably, E2 inhibited plaque formation and the induction of αSMA transcripts in female rat lenses but not in male rat lenses. E2 also inhibited the induction of αSMA in TGF-β2-incubated lenses from ovariectomized female rats.E2 prevented lens opacification and the induction of αSMA gene expression in female, but not male, lenses. This sex-specific difference may have implications for studies on the therapeutic use of estradiol for treatment of secondary cataract.