The miscibility of caffeine and cellulose acetate butyrate (CAB) was investigated as a function of caffeine (caf) content and correlated with in vitro drug release studies. Films of CAB/caf with caffeine contents larger than 5 wt% presented partial miscibility, as revealed by scanning electron microscopy, turbidity measurements and thermogravimetric analyses. CAB/caf with 2.5 wt% or less were homogeneous films. Favorable interactions between CAB and caffeine was evidenced by the decrease of the glass transition temperature of CAB in 28 °C and by Fourier transform infrared vibrational spectra of the films, which displayed shifts to higher wavenumbers of caffeine bands assigned to the stretching of conjugated C=O(6) and isolated C=O(2) carbonyl groups of 16 cm−1 and 9 cm−1, respectively. No drug was released from completely miscible systems, regardless of the external medium. Partially miscible CAB/caf systems showed a two-step release process: in the first 6 h the segregated portion of caffeine dissolved in the medium and a second one, when the release of drug located in the internal polymer matrix took place. After 48 h, at pH 7.4, the release of caffeine from CAB/caf 7 wt% was complete