The objective was to investigate the relationship between in vitro and in vivo release of commercial Risperdal^® Consta^® microspheres. A modified USP apparatus 4 method was used for accelerated and real-time in vitro release testing. The in vivo plasma profile (clinical data) reported for the product was deconvoluted for comparison with the in vitro release profiles. The in vivo profile differed from the real-time in vitro profile and was faster initially and then slower after approximately 30 days. This effect is considered to be due to differences in the in vivo conditions such as small interstitial volume, low pH and immune response. Accelerated in vitro release profiles obtained at temperatures (50 °C and 54.5 °C) above the microsphere glass transition temperature (Tg ∼ 48 °C) overlapped with the in vivo profile after time scaling. A linear in vitro–in vivo relationship was observed with correlation coefficients of 0.97 and 0.99 at 50 °C and 54.5 °C, respectively. The accelerated test performed below the Tg had a similar release profile to that of the real-time in vitro test. The accelerated tests performed above the Tg of the microspheres showed the potential to be used for in vivo performance prediction as well as for quality control purposes.