We modified synthetic isoprene rubber by means of the in situ generation of silica particles through the sol-gel process starting from tetraethoxysilane (TEOS) as an inorganic oxide precursor. Different reaction conditions were investigated with variations in the initial TEOS content, the reaction time of the sol-gel process, and the presence of a coupling/surfactant agent (octyltriethoxysilane). Organic-inorganic hybrid materials with a silica content up to 70 phr were obtained with the complete conversion of TEOS to silica for a long enough sol-gel reaction time. A very homogeneous dispersion of silica particles was observed in all cases together with a very good adhesion between the filler and matrix. The size of the in situ generated silica was controlled by the appropriate addition of octyltriethoxysilane. Swelling and extraction tests and dynamic mechanical analysis indicated that the vulcanization process of isoprene rubber was perturbed by the sol-gel process; this led to a slight decrease in the crosslinking degree. However, a significant reinforcing effect due to the presence of silica particles was observed for all of the investigated samples.