The aim of the study was to compare the efficacy of oral micronized progesterone when applied by the vaginal route. The comparative study of serum progesterone levels between oral and vaginal micronized progesterone administration was conducted in sixty female volunteers. The subjects were equally divided into two groups to receive the drug either via the oral or vaginal route. The subjects’ profiles showed that there was no significant difference in general characteristics between these two groups. The blood tests for estrogen and progesterone levels were performed on all volunteers before and after the drug administration. The data collected from the experiment revealed that the serum progesterone levels achieved by oral administration (5.06 ± 2.95 ng/ml) differed significantly (p < 0.001) from those achieved by vaginal administration (8.26 ± 4.09 ng/ml). The data also revealed that the serum progesterone levels of the oral administration group (4.23 ± 2.68 ng/ml) did not differ significantly (p = 0.925) from the other group (4.15 ± 3.40 ng/ml) when the serum estrogen level was less than 30 pg/ml. On the contrary, when the serum estrogen level was at least 30 pg/ml, there was a significant (p < 0.005) difference in the serum progesterone levels between these two groups (6.32 ± 2.99 ng/ml for the oral route and 9.76 ± 3.23 ng/ml for the vaginal route).