Background: There is an increasing trend of traffic accidents in the world in recent years. Road traffic injuries in Iran, caused 17994 deaths in 2012 - 13. Among these accidents, the most terrible one occurred on September 9, 2012 at 22:48 hour GMT, when two approaching buses had a head-on collision on 28-kilometer Tehran-Qom highway, killing 44 passengers on board and leaving 47 injurers. Objectives: This study aimed to assess factors, causes, and lessons learned from the two bus collision on the Tehran-Qom highway in Iran. Methods: This case study adopted qualitative approach, to explore the different scenarios of the crash focusing on content analysis. Focus Group Discussion, semi-structured individual interviews and review of documentations and evidence were the data sources. Data and evidence gathered from people’s experience and perceptions, such as officials and staffs of rescue teams, were analyzed. Results: After repeated analysis and comparison of data, three categories were explored (agent/host/environment causes, victims’ search and rescue, and psychosocial support). Inadequate bus supervision and driver’s behavior, lack of fire extinguishers, and rescue tools such as hammers in buses, and blocked doors contributed to increased casualties. Effective field assessment for incidence and decentralizing stand-by hospitals would help reduce casualties. Lack of effective coordination, lack of psychosocial support services for victims and participation of ‘lay people’ the scene, were key findings. Conclusions: Lessons learned: controlling per-second speed, improving vehicle manufacturing quality, re-training courses for drivers and the empowerment of rescuing people should help reduce human casualties during accidents. Lack of fire stations and fire extinguishing agent along the road outside cities are major problems. Common dispatch center with national emergency number is explicitly recommended for faster and more coordinated rescue services to reach the accidents scene. We also suggested instruction of psychosocial support for victims, survivors, and even rescuers during and after rescue process. Finally, persistent merge of existing rescue organizations, leading to the development of a national emergency management organization (NEMO) and national data collection system are highly recommended.