Current guidelines recommend that hormone therapy (HT) in postmenopausal women with a uterus include a progestin to protect against endometrial hyperplasia. However, many concerns relating to HT use appear to be related to the progestin component, including cardiovascular risk, breast stimulation, and irregular vaginal bleeding. Conjugated estrogens (CE) combined with the selective estrogen receptor modulator bazedoxifene (BZA) is a new progestin-free HT option for alleviating estrogen deficiency symptoms in postmenopausal women with a uterus for whom treatment with progestin-containing therapy is not appropriate. Five double-blind, randomized, placebo-controlled, phase 3 studies, known as the Selective estrogens, Menopause, And Response to Therapy (SMART) trials have investigated the efficacy of CE/BZA for relieving vasomotor symptoms (VMS), and effect on bone mass, as well as endometrial and breast safety in postmenopausal women. In a 12-week study, CE 0.45 mg/BZA 20 mg significantly reduced the number and severity of hot flushes compared with placebo at weeks 4 and 12. Unlike estrogen-progestin therapy (EPT), CE 0.45 mg/BZA 20 mg did not increase breast density compared with placebo. In clinical trials up to 2 years, CE/BZA had a favorable tolerability profile, demonstrated by amenorrhea rates similar to placebo. Vascular disorders including venous thromboembolic events (pulmonary embolism, retinal vein thrombosis, deep vein thrombosis, and thrombophlebitis) were rare events, occurring in less than 1 per 1000 patients. CE/BZA was associated with significantly higher incidences of amenorrhea and lower incidences of bleeding compared with CE/medroxyprogesterone acetate in 2 comparative trials. Therefore, CE 0.45 mg/BZA 20mg provides an effective, well-tolerated, progestin-free alternative to EPT for postmenopausal women with a uterus.