OBJECTIVES: The oral combined formulation of levonorgestrel with estradiol valerate (LNG+EV) has demonstrated to be effective on some postmenopausal symptoms. The availability of a transdermal HRT in sequential formulation with 17-beta-estradiol plus levonorgestrel (TSE2+TSLNG) induced us to do this control-study with the aim to evaluate the efficacy and safety of both oral and transdermal treatments. METHODS: At baseline, the psychological symptoms with the psychometric scale SCL-90, the bone resorption with the measurement of the urinary levels of pyridinoline and dexoxypirydinoline, and the insulin and lipid metabolism were assessed in 30 postmenopausal women (PMW) and in 18 premenopausal women. Then, the PMW women were randomly divided in three groups: group A (N=10) assumed EV+LNG, group B (N=10) did not assume any treatment, group C (N=10) was treated with TSE2+TSLNG. The length of the study was 12 months. The aforementioned assessments were repeated at different time-intervals up to the end of the study. RESULTS: The total score of SCL-90, the bone resorption, the levels of LDL-cholesterol, total-cholesterol and the parameters of insulin metabolism were higher in PMW than in premenopausal women. During the study, the SCL-90, the bone resorption, total-cholesterol, and LDL-cholesterol levels significantly decreased only in the groups A and C. By contrast, in the group B bone resorption significantly increased at the 12th month. During the treatments, insulin metabolism did not change in the groups A and B. In the group C the secretion of C-peptide and the C-peptide:insulin ratio after OGTT were significantly higher at the 12th month than before treatment. In all groups the endometrium thickness did not change during the study. CONCLUSION: A 12-month of either oral or transdermal HRT containing levonorgestrel seems to exert beneficial effects on the main postmenopausal symptoms without negative interferences on the endometrium.