The present study aimed to evaluate the short-term effects of a combination of isoflavones, lignans and Cimicifuga racemosa on acute climacteric-related symptoms in postmenopausal women in a double-blind, randomized, placebo-controlled trial performed at the menopause clinic of our department. Eighty healthy postmenopausal women were randomly assigned to two treatment groups - one receiving the combination (group A, n = 40), the other receiving calcium supplements (group B, n = 40) - for three cycles of 28 days. Climacteric-related symptoms were evaluated by the Kupperman index (KI) at baseline and after the three cycles of treatment. At baseline no significant difference was detected in KI between groups A and B; however, after three cycles of treatment, KI was significantly (p < 0.05) lower in group A compared with baseline and with group B. We conclude that the administration of a combination of isoflavones, lignans and C. racemosa already reduces acute climacteric symptoms in postmenopausal women after 3 months of treatment. This prompt effect is probably due to the different pharmacokinetic properties of isoflavones and lignans; isoflavones are absorbed faster than lignans, while lignans are removed later. The combination of these molecules can guarantee a better reduction of postmenopausal symptoms over a 24-h period.