Background An incident command structure is commonly used to manage responses to major incidents. In the hospital incident command structure, the medical officer in charge (MOC) is in a key position. The decision-making process is essential to effective management, but little is known about which factors influence the process. Therefore, the current study aimed to describe factors influencing decision-making of MOCs. Methods A conventional content analysis was conducted based on 16 individual interviews with medical doctors who had been deployed as MOCs at Swedish hospitals during major incidents. Results The results showed that the decision-making and re-evaluation process was a comprehensive analysis influenced by three categories of factors: event factors, including consequences from the type of event, levels of uncertainty and the circumstances; organizational factors, including the doctor’s role, information management and the response to the event; and personal factors, such as competence, personality and mental preparedness. Conclusions Reliable and timely information management structure enabling the gathering and analysis of essential information, a clear command structure and appropriate personal qualities were essential and contributed to successful MOCs decision making in major incidents.