Biodegradable heterografted molecular bottle brushes were prepared in two steps starting with a linear polyglycidol as a macroinitiator. First, ca. 45% of the polyglycidol hydroxy groups were grafted with e-caprolactone via enzymatic catalysis. Selective end capping of the hydroxy groups at the graft ends was achieved via enzymatic esterification with vinyl acetate or vinyl acrylate. Finally, poly(L-lactide) grafts were attached to the remaining polyglycidol hydroxy groups by chemically catalyzed ring-opening polymerization. The successful synthesis of the heterografted comb-shaped brushes was confirmed by NMR and SEC analyses. Additionally, the feasibility of microsphere formulation was described. © 2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.