AbstractPoly(hexyl‐substituted lactides) (PHLA) as new hydrophobic polyesters with controlled molecular weights and narrow distributions were synthesized by ring‐opening polymerization (ROP) using tin(II) 2‐ethylhexanoate (Sn(Oct)2) and benzyl alcohol as catalyst and initiator. Glass transition temperatures (Tg) and zero shear viscosities (η0) at 25°C could be modulated from Tg= −42°C to −10°C and 40 to 4850 Pa s, respectively, by varying the polymer molecular weight and the number of hexyl groups along the polymer chain. Degradation studies were performed in terms of both mass and molecular weight loss in the course of time. The degradation mechanism is shown to be of the “bulk erosion” type, and comparable to standard poly(D,L‐lactide) (PLA). Despite the increased steric hindrance in the poly(monohexyl‐substituted lactide) (PmHLA) due to the hexyl side groups, its degradation rate at pH 7.4 and 37°C was found to be slightly higher than observed for the analogue standard PLA. This could be attributed to the flexible rubbery state of the hexyl‐substituted polymer (Tg∼−15°C) at the physiological temperature, which is favoring the degradation in comparison to the rigid and glassy standard PLA (Tg∼40°C). In contrast, degradation studies performed at 60°C, where both polymers are above their glass transition temperature, confirmed that the degradation rate is lower for the sterically more hindered PmHLA. The degradation products were analyzed by ESI‐MS. Hydrolysis lead first to the corresponding oligo‐ester fragments and finally to the nontoxic 2‐hydroxyoctanoic acid and lactic acid. Tetracycline was tested as a model drug for release studies. This drug was found to be released faster and in higher amounts in its active form from the PHLA matrix than from standard PLA. The results presented in this work demonstrate the potential of these hydrophobic polylactide‐based semisolid materials as an alternative to conventional PLA/PLGA for injectable drug delivery systems. © 2006 Wiley Periodicals, Inc. J Biomed Mater Res, 2007