Objectives: To compare the effect of low-dose transdermal estradiol (E2)/norethisterone acetate (NETA) patches (Estalis 25/125) with low-dose oral E2/NETA (Activelle) in terms of cardiovascular biochemical markers after 12 and 52 weeks of treatment in postmenopausal women with intact uteri. Methods: Patients were randomized to receive either transdermal E2/NETA (delivering daily doses of E2 25µg and NETA 125µg; applied every 3–4 days) or oral E2/NETA (E2 1mg and NETA 0.5mg; given daily) in this open-label study. Assessment of the following markers or their stable metabolites in serum or urine: P-selectin, ICAM–1, VCAM–1, MCP–1, MMP–9, homocysteine, cGMP, serotonin, prostacyclin, thromboxane, and urodilatin. Results: Significant decreases were found for P-selectin, ICAM–1, MCP–1 and homocysteine for both HRT regimens as compared to baseline. MMP–9 was increased only by oral HRT. The urinary concentrations of cGMP, the ratio of prostacyclin to thromboxane metabolite and the serotonin metabolite were significantly increased for both HRT application modes although the oral application showed a significantly greater increase than the transdermal one with respect to baseline. Urodilatin excretion was only increased by the oral regimen. Conclusions: Low-dose transdermal and oral HRT using estradiol and norethisterone acetate elicit favourable effects on cardiovascular biochemical markers. For most marker the changes found were in a similar magnitude with respect to baseline, however, in some cases oral HRT led to a significant higher alteration while in other cases the transdermal formulations seems to provide greater benefits.