A sort of hydrophobic poly(dodecyl/methylsilsesquioxane) nanoparticles (PDMSQ NPs) were prepared by the hydrolysis-condensation reaction in ethanol/H2O mixed solutions. Methyltriethoxysilane (MTES) and dodecyltrimethoxysilane (DTMS) were used as precursors and sodium hydroxyl as the catalyst. FT-IR and XPS were utilized to characterize the structure of PDMSQ NPs. DLS, FE-SEM and TGA were applied to investigate its average particles size, micro-morphology and thermal stability. Results indicated that the carbon content was highly as 41.73% at the surface of PDMSQ NPs and signal at the binding energy of 103.04 eV was attributed to the characteristic signal of Si 2p from the PSQ. Hence, PDMSQ NPs had the nanosphere structure with Si-O bond as the skeleton and lots of dodecyl and methyl groups at its surface. While the weight loss of PDMSQ NPs was 5% and the corresponding temperature was 351 ℃, this demonstrate that thermal stability of the PDMSQ NPs was excellent. When the molar ratio of MTES to DTMS was amongst 10∶1.0~10∶1.4 and the reaction temperature was 60 ℃, the obtained PDMSQ NPs had the smooth surface with the regularly sperical and monodispersed patterns by the FE-SEM observation. Water contact angle on its surface attained 168° and finally the formation mechanism was also proposed.