Objective: To evaluate the possible DNA damage in peripheral blood leukocytes of postmenopausal women under different hormone replacement therapies (HRT), comet assay, a standard method for assessing genotoxicity has been used. Method: 46 women were categorized in three groups-Group A: 15 surgical menopausal women who underwent surgery for benign conditions, receiving conjugated equine estrogen, 0.625 mg/day (CEE) for 2.3 +/- 1.5 years, Group B: 16 spontaneous menopausal women receiving conjugated equine estrogen, 0.625 mg/day plus medroxyprogesteron acetate, 5 mg/day (CEE + MPA) for 2.4 +/- 1.0 years and Group C: 15 spontaneous menopausal women receiving tibolone, 2.5 mg/day for 2.4 +/- 1.3 years. Control group consisted of 15 spontaneous menopausal women who never had HRT. Results: Significant differences in terms of DNA damage were observed between Group A and B with controls as mean total comet scores 23.93 +/- 15.84, 19.44 +/- 6.19 and 10.07 +/- 2.40, but no significance (P > 0.05) were detected between Group C and controls as mean total comet scores 12.07 +/- 3.65 and 10.07 +/- 2.40, respectively. Conclusion: Reduced DNA damage were observed with tibolone compared to CEE or CEE + MPA therapy. Studies of this approach are needed. (c) 2004 Elsevier Ireland Ltd. All rights reserved.