Acute ethanol lowers blood pressure (BP) and cardiac output in proestrus and after chronic estrogen (E₂) replacement in ovariectomized (OVX) female rats. However, whether rapid nongenomic effects of estrogen mediate these hemodynamic effects of ethanol remained unanswered. To test this hypothesis, we investigated the effect of ethanol (0.5 or 1.5 g/kg; i.v.) on left ventricular (LV) function and oxidative markers in OVX rats pretreated 30 min earlier with 1 μg/kg E₂ (OVXE₂) or vehicle (OVX) and in proestrus sham-operated (SO) rats. In SO rats, ethanol caused significant and dose-related reductions in BP, rate of rise in LV pressure (LV dP/dtmax), and LV developed pressure (LVDP). These effects of ethanol disappeared in OVX rats and were restored in OVXE₂ rats suggesting rapid estrogen receptor signaling mediates the detrimental effects of ethanol on LV function. Ex vivo studies revealed that the estrogen-dependent myocardial dysfunction caused by ethanol was coupled with higher left ventricular: (i) generation of reactive oxygen species (ROS), (ii) expression of malondialdehyde (MDA) and. 4-hydroxynonenal (4-HNE) protein adducts, (iii) phosphorylation of protein kinase B (Akt) and extracellular signal-regulated kinases (ERK1/2), and (iv) catalase activity. ERK1/2 inhibition by PD98059 (1 mg/kg i.v.) abrogated the myocardial dysfunction, hypotension and the elevation in myocardial ROS generation caused by ethanol. It is concluded that rapid estrogen receptor signaling is implicated in cellular events that lead to the generation of aldehyde protein adducts and Akt/ERK1/2 phosphorylation, which ultimately mediate the estrogen-dependent LV oxidative stress and dysfunction caused by ethanol in female rats.