Purpose: The aim of the present study was to evaluate the effects of tibolone on inter-cellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), inter-cellular adhesion molecule-2 (ICAM-2) and P-selectin levels in healthy postmenopausal women. Methods: This prospective study included 25 postmenopausal women, complaining of hot flashes, assigned in two groups. Fifteen women received tibolone (dosage of 2.5 mg per day for six months) and ten women did not receive any therapy, according to their personal preference. Basal control included complete medical history, anthropometrics, clinical examination, and blood sampling to perform hormonal, biochemical, hematological testing and ICAM-1, ICAM-2, VCAM-1 and P-selectin measurements. Evaluation was repeated in three and six months. Results: There was no significant difference in ICAM-1, VCAM-1, ICAM- 2, P-selectin, homocysteine, total cholesterol, HDL, LDL, and triglyceride concentrations between the women of the two groups after either three or six months of treatment. However, a significant reduction in the frequency and intensity of hot flashes was noted in both groups. Conclusions: Tibolone does not have any adverse effects on cell adhesion molecule levels which primarily affect atherosclerotic processes or on triglyceride and homocysteine concentrations. These results may support the view that tibolone could be considered a safe treatment, regarding its impact on the endothelium, in healthy postmenopausal women.