A procedure for preparing 6-O-alkyl erythromycin compounds having the formula: wherein R1 is a loweralkyl group, R2 and R3 an independently hydrogen or a hydroxy-protecting group, except that R2 and R3 may not both be hydrogen simultaneously; Y is oxygen or a specifically substituted oxime; and Z is hydrogen, hydroxy or protected-hydroxy; by reaction of the compound wherein R1 is hydrogen with an alkylating reagent, is the presence of a strong alkali metal base and also in the presence of a weak organic amino base, in a suitable stirred or agitated polar aprotic solvent, or a mixture of such polar aprotic solvents maintained at a reaction temperature and for a period of time sufficient to effect alkyation.