The complexation of small interfering ribonucleic acid (siRNA) with a series of specifically designed block copolymers consisting of the hydrophilic, nonimmunogenic monomer N-(2-hydroxypropyl)methacrylamide ( HPMA) and the cationic monomer N-[3-(dimethylamino)propyl]methacrylamide (DMAPMA) has been investigated for potential siRNA stabilization and delivery applications. Specific compositions of poly( HPMA-b-DMAPMA) copolymers were synthesized via aqueous reversible addition-fragmentation chain transfer (RAFT) polymerization and characterized using aqueous size exclusion chromatography with multiangle laser light scattering (SEC-MALLS) and H-1 NMR spectroscopy. The degree of soluble complex formation between a model siRNA and the polymers was determined by centrifugal membrane filtration experiments and quantitated by scintillation counting of P-32 ATP-labeled siRNA to determine complex solubility and to estimate the degree of complexation relative to cationic and neutral block lengths. Dynamic and static light scattering methods were employed to determine the hydrodynamic radii, molecular weights, and second virial coefficients of the complexes and to demonstrate their unimodal size distributions. In vitro enzymatic degradation studies of selected siRNA/block copolymer complexes were conducted to demonstrate the enhanced stability of the siRNA/poly(HPMA-b-DMAPMA) complexes. Furthermore, the siRNA/polymer complexes dissociate slowly under gel electrophoresis conditions. Therefore, the siRNA/polymer complexes demonstrate some highly desirable properties for potential applications in therapeutic siRNA stabilization and delivery.