Polyhedral oligosilsesquioxane (POSS)-containing amphiphilic poly(vinyl alcohol) (PVA) hybrids (PVA-POSS hybrids) were synthesized by urethane linkage between the hydroxyl groups of PVA and the monoisocyanate group of POSS macromers. The hydrophobicity of the amphiphilic PVA-POSS hybrids was varied by changing the incorporated amounts of the hydrophobic POSS macromers, resulting in control over water resistance. The synthesized amphiphilic PVA-POSS hybrids were characterized by H-1 NMR, FT-IR, DSC, and TGA and revealed modified thermal stability and solubility depending on the incorporated amounts of POSS macromers. That is, modification in both solid form and solution is observed, which is attributed to the bulkiness and hydrophobicity of POSS moieties. As a result, the amphiphilic PVA-POSS hybrids with the molar ratio of POSS macromer to -OH mole of PVA ranging from 1.0 to 15.0 could be obtained. Amphiphilic PVA-POSS hybrids showed microstructural features characteristic structure of two separate crystalline components, that is, the dual system of PVA and POSS crystalline phases. In addition, the electrospun nanofibers of PVA-POSS hybrids suggest a new method to enhance/control the water resistance of PVA nanofibers without cross-linking.