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Abstract: Objective: Cardiac mass increases with age and with declining estradiol serum levels in postmenopausal women. Although the non-selective estrogen receptor-α and -β agonist 17β-estradiol attenuates cardiac hypertrophy in animal models and in observational studies, it remains unknown whether activation of a specific estrogen receptor subtype (ERα or ERβ) might give similar or divergent results. Therefore, we analyzed myocardial hypertrophy as well as cardiac function and gene expression in ovariectomized, spontaneously hypertensive rats (SHR) treated with the subtype-selective ERα agonist 16α-LE2 or 17β-estradiol. Methods and Results: Long-term administration of 16α-LE2 or 17β-estradiol did not affect elevated blood pressure, but both agonists efficiently attenuated cardiac hypertrophy and increased cardiac output, left ventricular stroke volume, papillary muscle strip contractility, and cardiac α-myosin heavy chain expression. The observed effects of E2 and 16α-LE2 were abrogated by the ER antagonist ZM-182780. Improved left ventricular function upon 16α-LE2 treatment was also observed in cardiac MRI studies. In contrast to estradiol and 16α-LE2, tamoxifen inhibited cardiac hypertrophy but failed to increase α-myosin heavy chain expression and cardiac output. Conclusions: These results support the hypothesis that activation of ERα favorably affects cardiac hypertrophy, myocardial contractility, and gene expression in ovariectomized SHR. Further studies are required to determine whether activation ERβ mediates redundant or divergent effects. [Copyright &y& Elsevier]