Individuals who require hospitalization after traumatic injuries are at increased risk for developing posttraumatic stress disorder (PTSD); however, few early behavioral interventions have been effective at preventing PTSD within this population. The aim of this pilot study was to assess the feasibility and effectiveness of modified prolonged exposure therapy (mPE) to prevent PTSD and depression symptoms among patients hospitalized after a DSM‐5 single‐incident trauma. Hospitalized patients were eligible if they screened positive for PTSD risk. Participants (N = 74) were randomly assigned in a parallel‐groups design to receive mPE (n = 38) or standard of care treatment (SoC; n = 36) while admitted to the hospital after a traumatic injury. Individuals randomized to the intervention condition received one (42.1%), two (36.8%), or three sessions (15.8%) of mPE, mainly depending on length of stay. There were no significant differences between groups regarding PTSD or depression severity at 1‐ or 3‐months posttrauma, except for more PTSD diagnoses in the intervention group after 1 month, ϕ = −.326. Intervention differences were nonsignificant when we took baseline PTSD symptoms and the nonindependence of the repeated measurements within the data into account. No adverse events were reported. Overall, mPE was no more effective than SoC for hospitalized, traumatic injury survivors with a high PTSD risk. The results may point to a need for a stepped‐care approach, where intervention protocols focus on first briefly treating individuals who are actively exhibiting acute stress reactions, then extensively treating those whose symptoms do not decrease over time.