© 2014 Society of General Internal Medicine BACKGROUND: Improvements in hospital patient safety have been made, but innovative approaches are needed to accelerate progress. Evidence is emerging that microsystem approaches to quality and safety improvement in hospital care are effective. OBJECTIVE: We aimed to evaluate the effects of a multifaceted, microsystem-level patient safety program on clinical outcomes and safety culture on inpatient units. DESIGN: A 1-year prospective interventional study was conducted, followed by a 6-month sustainability phase. SETTING AND PARTICIPANTS: Four medical and surgical inpatient units within an academic university medical center were included, with registered nurses and residents representing study participants. INTERVENTIONS: In situ simulation training; debriefing of medical emergencies; monthly patient safety team meetings; patient safety champion role; interdisciplinary patient safety conferences; recognition program for exemplary teamwork. OUTCOMES: Hospital-acquired severe sepsis/septic shock and acute respiratory failure; unplanned transfers to higher level of care (HLOC); weighted risk-adjusted mortality. Safety culture was measured using a widely accepted, validated survey. RESULTS: Rates of hospital-acquired severe sepsis/septic shock and acute respiratory failure decreased on study units, from 1.78 to 0.64 (p = 0.04) and 2.44 to 0.43 per 1,000 unit discharges (p = 0.03), respectively. The mean number of days between cases of severe sepsis/septic shock increased from baseline to the intervention period (p = 0.03). Unplanned transfers to HLOC increased from 715 to 764 per 1,000 unit transfers (p = 0.08). The weighted risk-adjusted observed-to-expected mortality ratio on all study units decreased from 0.50 to 0.40 (p < 0.001). Overall scores of safety culture on study units improved after the 1-year intervention, significantly for nurses (p < 0.001), but not for residents (p = 0.06). Scores significantly improved in nine of twelve survey dimensions for nurses, compared to in four dimensions for residents. CONCLUSION: A multifaceted patient safety program suggested an association with improved hospital-acquired complications and weighted, risk-adjusted mortality, and improved nurses’ perceptions of safety culture on inpatient study units.