Purpose of investigation: The aim of this prospective randomized study was to evaluate a red clover based isoflavones supplementation in the treatment of climacteric syndrome and its effects on cardiovascular risk serum profile. Materials and Methods: The study included 150 healthy postmenopausal women that were randomly assigned to receive phytoestrogens tablets, amounting in a total daily intake of 60.8 mg red clover isoflavones plus 19.2 mg soy isoflavones (n = 75), or placebo (n = 75). The authors evaluated teh following: daily number of hot flushes and Kupperman Index at baseline and after one and three months; serum total, high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol, triglycerides, prothrombin time (PT), partial thromboplastin time (PTT), fibrinogen, and antithrombin III (ATIII) at baseline and after three and six months. Results: One hundred twenty-eight patients completed the study: 67 in the active group and 61 in the placebo group. The treatment led to a progressive significant reduction (p < 0.05) of the number of hot flushes in the active group compared to placebo already after one month, while Kupperman Index was statistically reduced after three months. No significant variation in total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides, PT, PTT, fibrinogen, and ATIII were found. Conclusion: The present findings suggest that a red clover based isoflavones supplementation in healthy postmenopausal women is promptly effective on climacteric syndrome, improves neurovegetative symptoms, safe on cardiovascular risk serum profile, and does not modify lipids and coagulation.