The morphology, miscibility, and specific interactions of paclitaxel (PTx) with a family of polyhedral oligosilsesquioxane (POSS)-based biodegradable thermoplastic polyurethanes (POSS TPUs) were investigated systematically using wide-angle X-ray diffraction (WAXD), differential scanning calorimetry (DSC), and Fourier transform infrared spectroscopy (FTIR). These POSS TPUs incorporate an alternating multiblock structure formed by POSS hard segments and the soft segments composed of polylactide/caprolactone copolymer (P(DLLA-co-CL)). They feature variable poly(ethylene glycol) (PEG) content from 0 to 14 wt % through adjusting the poly(ethylene glycol) (PEG)molecular weight in P(DLLA-co-CL) soft segments of fixedmolarmass ofM _ n=12kg/mol and further to 52wt%utilizingpurePEGM _ n=1kg/mol in the soft segments.UsingWAXD, it was found that PTx is amorphous in all proportions in the PTx/POSS TPU blends prepared using a solutioncastingmethod. Interestingly, the PTx not only exhibits excellent miscibility in all of these PTx/POSSTPUblends over the whole range of the drug concentration, but also serves as an antiplasticizer by increasing the blend Tg gradually from the polymerTg up to theTg of amorphous PTx. TheTg-composition dependences in these blends were well fitted by theGordon-Taylor equation. The glass transition breadth of the blends increases significantly only for drug concentrations higher than 50 wt % for most of the POSS TPUs, suggesting some spatial heterogeneity at these high drug concentrations. On the other hand, the slight increment of the blend melting temperature,Tm, and latent heat,ΔH, indicates enhanced phase separation between the POSS hard segments and the TPU soft segments upon drug incorporation. Gordon-Taylor analysis and FTIR results confirm that the PEG incorporated in the POSS TPUs exhibits strong H-bonding interactions with the PTx. Although PEG can promote the favorable interactions in the PTx/POSS TPU blends, we showed that the more hydrophobic LA/CL repeat units are still required in the soft segments in order to achieve molecular-level miscibility. This systematic investigation of the PTx/POSS TPU systems may be of great value to design plasticizer/antiplasticizer for new polymermaterials with controlled and tailored properties, especially for those PLAor PCL-based biodegradable polymer systems.