New fatty polynic (linoleic, linolenic, arachidonic, linoelaidic) mono esters of erythromycin A have been synthesized by using various reagents such as acyl chloride, carboxylic acid anhydride, and mixed carbonic anhydride. These different ways of activating the fatty acid allowed a regioselectivity of esterification at position 2' of the desosamine ring or position 4" of the cladinose ring of erythromycin A. The in vitro antibacterial properties of these new esters against members of the resident flora of the human skin were determined and compared with those of erythromycin A. The number and the stereochemistry of the double bonds seem to play a crucial role in the expression of thei n vitro antibacterial activity.