To evaluate the effects of oral estradiol given with either oral or intravaginal micronized progesterone (P4) on risk biomarkers for breast cancer in a postmenopausal monkey model. This experiment was a two-way crossover study in which 20 ovariectomized adult female cynomolgus macaques were treated (in equivalent doses for women) with oral estradiol (1 mg/d) + oral micronized P4 (200 mg/d) or intravaginal P4 delivered by Silastic rings (6- to 10-mg/d release rate). Hormone treatments lasted 2 months and were separated by a 1-month washout period. The primary outcome measure was breast epithelial proliferation. Serum P4 concentrations were significantly greater in subjects receiving oral P4 (10.9 ng/mL) compared with intravaginal P4 (3.8 ng/mL) at 2 to 3 hours after oral dosing (P<0.0001) but not at 24 to 28 hours after oral dosing (2.9 ng/mL for oral P4 vs 3.2 ng/mL for intravaginal P4 at 2 months, P=0.19). Serum estradiol concentrations were significantly lower after oral P4 than after intravaginal P4 (P<0.05 for all time points). Oral P4 resulted in significantly decreased body weight (-2.5%) compared with intravaginal P4 (+3.6%) (P=0.0001). Markers of breast proliferation, sex steroid receptor expression, and endometrial area did not differ significantly between oral P4 and intravaginal P4 treatments (P>0.1 for all). Despite different pharmacodynamic profiles, oral and intravaginal P4 had similar effects on biomarkers in the postmenopausal breast.