Hollow glass microspheres (HGMS) have been widely used in the hydrocarbon industry for cementing wells with low-density slurries. These consist of amorphous siliceous hollow spheres filled with gas, providing a low-density material with high strength. The present study aims to characterize the interaction between HGMS and the cement paste, focusing mainly on the development of the pozzolanic activity, given the nature of amorphous silica. Therefore, two HGMS of different crush strength levels were studied. HGMS were used as a replacement of total cementitious binder at 10% by weight of cement. The pozzolanic activity was measured within the modified Chapelle test, the portlandite quantification from thermogravimetric analysis, and the strength activity index. Additionally, isothermal calorimetry analysis, X-ray diffraction patterns and scanning electron microscopy images were obtained. Results demonstrated that HGMS interact with the cement paste initially as nucleation agents and later with a pozzolanic reaction, presenting an activity comparable to that of metakaolin or fly ash.