The estrogen-related receptor alpha (Esrra) is an orphan nuclear receptor with strong homology to estrogen receptor alpha (ERα), whereas it exhibits estrogen-independent constitutive transcriptional activity to regulate a number of genes involving in cellular energy metabolism. Esrra is broadly expressed throughout the body including those metabolically active tissues such as skeletal muscles, heart, brown adipose tissues, kidney, and brain. While previous reports showed that Esrra knockout (KO) mice were hypotensive and resistant to high fat diet-induced obesity (DIO), systemic understanding of the roles of Esrra in cardiometabolic control is limited. We therefore performed a variety of metabolic and cardiovascular measures to evaluate the cardiometabolic consequences of mice lacking Esrra globally. Our results revealed that Esrra KO mice were hypoactive and were resistant to DIO mainly due to decreased food intake. Despite of lower body weight and plasma leptin level, female Esrra KO mice tend to have elevated blood glucose level (p=0.08) without notable changes of insulin and glucagon levels. Non-invasive blood pressure measurement by tail-cuff sphygmomanometer showed that male Esrra KO mice had significantly lower blood pressure when the measurement was performed during light period (WT vs. KO: 99.8±1.4 vs. 93.9±1.8 mmHg, p<0.05). On the other hand, the blood pressure measured during dark period was significantly lower in female, but not male, Esrra KO mice compared to their WT littermates (106.1±1.8 vs. 98.8±1.5 mmHg, p<0.05). Pulse wave velocity test showed that vascular stiffness was comparable between genotypes in both genders. Echocardiographic measurements revealed that the ejection fraction of male, but not female, KO mice was significantly higher than that of WT littermates (WT vs. KO: 75.2±0.02% vs. 85.4±0.01%, P<0.01), while female KO mice did not show any significant changes. These results indicate a multifaceted role of Esrra in the regulation of metabolic and cardiovascular functions likely in a gender- and circadian cycle-dependent manner. Future studies with conditional deletion approach are necessary to tease apart complex roles of Esrra in distinct cardiometabolic processes.