The in vitro degradation of polylactic acid of different weight average molecular weight (M w ) in microspheres containing variable amounts of methadone base (between 17 and 47%) was studied using the degradation index (DI), polidispersivity (pd) and molecular weights distribution. Both pd and DI are independent of initial methadone content and increase with M w polymer, showing values of DI around 6.6 for the high M w and 2.9 for the lowerM w . The distribution functions in the number of the molecular weights during the degradation assays indicate the presence of different break mechanisms for high and low molecular weight chains. A semiempiric model is proposed to explain the evolution of M n during degradation in function of the number of bonds available for their breaking and hydrolysis rate constant. The first parameter ranges between 2.35 and 6.65 in function of M w ; the hydrolysis rate constant is independent of M w and equal to 0.020 h - 1 (SD = 0.011 h - 1 ).