Microspheres of poly(vinyl alcohol) (PVA) and hydroxyethyl cellulose (HEC) were prepared as semi-interpenetrating networks (IPNs), crosslinked with glutaraldehyde and used in controlled release of theophylline (THP), an anti-asthmatic drug. Formulations were characterized by X-ray diffraction (XRD) to understand uniform distribution of THP, Fourier transform infrared (FTIR) spectroscopy to understand chemical interactions, universal testing machine (UTM) for mechanical stability, and scanning electron microscopy (SEM) for investigating the morphology of the microspheres produced. SEM indicated smooth surfaces of the microparticles and sizes of around 10-15 mu m giving high encapsulation efficiency up to 69%. Equilibrium uptake performed in double distilled water and in vitro release studies performed in 1.2 and 7.4 pH buffer media indicated the effect of extent of crosslinking and HEC content of the semi-IPN matrix on the release of THP that was extended up to 12 h. Analysis of in vitro results using empirical equation suggested a deviation from the Fickian transport. Drug diffusion was estimated from the Fick's diffusion equation for spherical geometry. Kinetics of drug release followed the Higuchi square root equation, indicating that release is diffusion-controlled. (C) 2010 Wiley Periodicals, Inc. J Appl Polym Sci 117: 1361-1370, 2010