BACKGROUND: Patient safety remains a national priority, but the role of disease-specific characteristics in safety is not well characterized. METHODS: We identified potentially preventable medical injuries using patient safety indicators (PSIs) and annual data from the Nationwide Inpatient Sample between 2003 and 2007. We compared the rate of selected PSIs among patients hospitalized with and without sepsis. Among patients with sepsis, we also compared PSI rates across severity strata. Using multivariable case-control matching and regression analyses, we estimated the excess adverse outcomes associated with PSI events in patients with sepsis. RESULTS: Patients hospitalized with sepsis accounted for 2% to 4% of hospital discharges; however, they accounted for 9% to 26% of all potential medical injuries. PSI rates varied considerably; among patients hospitalized for sepsis, they were lowest for accidental puncture or laceration and highest for postoperative respiratory failure. Nearly all PSI rates were higher among patients with sepsis compared with patients without sepsis. Among those with sepsis, most PSI rates increased as sepsis severity increased. Compared with matched sepsis control subjects, increased length of stay and hospital charges were associated with PSI events in sepsis cases. However, only decubitus ulcer, iatrogenic pneumothorax, and postoperative metabolic and physiologic derangement or respiratory failure were associated with excess mortality. CONCLUSION: Patients hospitalized for sepsis, compared with the general hospital population, were at a substantially increased risk of potential medical injury; their risk rose as disease severity increased. Future patient safety efforts may benefit from focusing on medically vulnerable populations.