Smoke is the most fatal factor that affects the occupants and goods when fire takes place. As it reduces visibility and can cause fatalities by asphyxiation. This research presents a numerical study of smoke spread in a large mosque. This research investigates the effect of heat release rate on the studied parameters which include visibility, smoke layer height, carbon monoxide concentration, smoke layer temperature and evacuation time as well as the effect of fire location and natural ventilation location on the same investigated parameters. Fire Dynamic Simulator (FDS) version 5.5.3 is utilized to simulate fire propagation in a 50 m long, 42 m wide and 32 m height of a large domed mosque that is divided into main hall for men and two identical floors for women. The fire is caused by an electric short circuit on ceiling air conditioners. Results shown in the paper indicated that, as a result of increasing heat release rate the tenable conditions are worsened where the visibility is reduced, carbon monoxide concentration is increased and the temperature as well increased at the human level. Therefore the evacuation time is increased with the increase of heat release rate. Also results show that changing fire location has a great effect on the studied parameters. When fire takes place at the center of the mosque the smoke spread is much more than that one when fire takes place at the corner of the mosque. Finally, the results show that the best positions of the natural vents are to be placed at the ceiling where tenable conditions are improved at the human level.