Clay formations are present in reservoirs and earthquake faults, but questions remain on their mechanical behavior, as they can vary from ductile (aseismic) to brittle (seismic). An experiment, at a scale of 10 m, aims to reactivate a natural fault by fluid pressure in shale materials. The injection area was surrounded by a dense monitoring network comprising pressure, deformation, and seismicity sensors, in a well-characterized geological setting. Thirty-two microseismic events were recorded during several injection phases in five different locations within the fault zone. Their computed magnitude ranged between −4.3 and −3.7. Their spatiotemporal distribution, compared with the measured displacement at the injection points, shows that most of the deformation induced by the injection is aseismic. Whether the seismicity is controlled by the fault architecture, mineralogy of fracture filling, fluid, and/or stress state is then discussed. The fault damage zone architecture and mineralogy are of crucial importance, as seismic slip mainly localizes on the sealed-with-calcite fractures which predominate in the fault damage zone. As no seismicity is observed in the close vicinity of the injection areas, the presence of fluid seems to prevent seismic slips. The fault core acts as an impermeable hydraulic barrier that favors fluid confinement and pressurization. Therefore, the seismic behavior seems to be strongly sensitive to the structural heterogeneity (including permeability) of the fault zone, which leads to a heterogeneous stress response to the pressurized volume.