Abstract: The electronic structures and conformations of non-polar-substituted 4-n-propyl-fentanyl and polar substituted 4-methoxymethyl-fentanyl and 4-methoxycarbonyl-fentanyl were investigated by the method of quantum mechanics. The results showed that the cause of effect of 4-substituent on biological activity not that change of conformations but that electronic factors. The 4-non-polar-substituents have not con-tribution upon increase of activity. The 4-polar-substituents form new additional negative electronic region, which may be the main assistant site interacting with receptor, the additional negative electrostatic potential region may interact with receptor at a new site or the site in common with amide oxygen. It is no doubt that the additional negative electrostatic potential field generated by the 4-polar-substituent dramatically increases the analgesic activity of the fentanyl derivatives.