Two series of 6alpha- and 6beta-phenylaliphatic-substituted androst-4-ene-3,17-diones (3 and 5) were synthesized as aromatase inhibitors to gain insights of structure-activity relationships of varying the n-alkyl moiety (C2 to C5) of the 6-phenylaliphatic substituents to the inhibitory activity. All of the inhibitors synthesized inhibited human placental aromatase in a competitive manner with apparent Ki values ranging from 16 to 115 nM. The 6alpha-phenethyl analog 3a and the 6beta-phenbutyl analog 5c (Ki=16 nM for the two inhibitors, respectively) were the most potent inhibitors in each series. The inhibitory activities of the 6beta-substituted steroids 5 except for the phenethyl compound 5a were more powerful than those of the corresponding 6alpha-isomers 3. Elongation of the alkyl moiety of the 6-substituent of the 6alpha-phenethyl steroid 3a up to five methylene units decreased affinity to aromatase in all cases, whereas the addition of two more methylene units to the 6-side chain of the 6beta-phenethyl analog 5a increased the affinity in relation to carbon number of the 6-substituent. These results along with molecular modelling with the PM3 method, would give a new information about the formation of thermodynamically stable enzyme-inhibitor complex in a hydrophobic binding pocket in the active site of aromatase.