The paper presents a numerical study on the interaction between two water sprays and smoke generated by a fire in a confined and mechanically-ventilated enclosure of 4.88 m × 8.67 m × 3.90 m (height). The fire source is a 1.2 m × 1.0 m × 0.6 m propane burner, generating a well-controlled heat source of 292 kW. The mechanical ventilation consists of an inlet and an extraction duct delivering each a flow rate of about 2500 m3/h. The two nozzles deliver a total flow rate of 109 l/min with a volume-median droplet diameter of about 470 μm. The CFD simulations carried out with the Fire Dynamics Simulator (FDS 6.7.9) show a very good agreement with the experimentally measured room pressure at quasi-steady state. The under-pressure peak of −993 Pa, occurring upon activation of the water spray system, is underpredicted by 25%. The overall thermal behavior is well-predicted. Nevertheless, the water spray mixing-induced loss of thermal stratification appears to be more pronounced in the CFD simulations, with over-predicted gas temperatures near the floor. The fraction of heat absorbed by the water at steady state is underestimated by 34%. The loss of chemical stratification upon water activation is well-predicted.