Firefighting is a demanding occupation, laden with hazardous exposures which result in traumatic injuries. Little epidemiologic evidence exists quantifying these factors, however. We conducted an incident-level case-control study of National Fire Incident Reporting System data of the association between firefighter injury and incident characteristics. Risk factors included 5 or more alarms (OR = 3.85; 95% CI, 3.32–4.48), number of stories (>3 vs. ground level OR = 2.49; 95% CI, 1.43 to 1.55), and at least one civilian injury (OR = 3.69; 95% CI, 3.55–3.84). Risk of injury was reduced for fires originating 49 feet and higher (OR = 0.57; 95% CI, 0.49–0.66). This analysis suggests that fireground-specific situations such as the number of stories or a civilian injury increase the risk of injury. Given the danger of firefighting, the identification of risk factors through epidemiologic methods is vital to developing safety measures.