OBJECTIVE The aim of this study was to evaluate low-dose synthetic conjugated estrogens A (SCE-A) cream administered twice weekly for the treatment of moderate to severe vulvovaginal atrophy (VVA) in a symptomatic postmenopausal population. METHODS In a multicenter, double-blind, randomized, placebo-controlled study, 305 women with symptoms of VVA were treated with either 1 g SCE-A cream (n = 150) or matching placebo (n = 155) for a period of up to 12 weeks. Participants had to have a vaginal pH of greater than 5, less than or equal to 5% superficial cells on a vaginal smear, and at least one of five symptoms of VVA (dryness, soreness, irritation, pain with intercourse, and bleeding after intercourse) that was moderate or severe in intensity. Women had to select one moderate or severe symptom as the most bothersome. RESULTS Efficacy was assessed at 2, 3, 4, 8, and 12 weeks and included the change from baseline in the severity of the most bothersome symptom (MBS), maturation index, and pH. Most women identified vaginal dryness as the MBS (48%) followed by pain with intercourse (31.3%). A statistically significant increase in the maturation index and significant decreases in pH and severity of the MBS were observed for those treated with SCE-A vaginal cream compared with placebo. CONCLUSIONS A low dose (1 g = 0.625 mg) of SCE-A vaginal cream administered twice weekly was shown to be effective compared with placebo in treating VVA in postmenopausal women for the three coprimary efficacy measures of maturation index, pH, and severity of the MBS.