IMPORTANCE Ventilator bundles, including head-of-bed elevation, sedative infusion interruptions, spontaneous breathing trials, thromboprophylaxis, stress ulcer prophylaxis, and oral care with chlorhexidine gluconate, are ubiquitous, but the absolute and relative value of each bundle component is unclear. OBJECTIVE To evaluate associations between individual and collective ventilator bundle components and ventilator-associated events, time to extubation, ventilator mortality, time to hospital discharge, and hospital death. DESIGN, SETTING, AND PARTICIPANTS This retrospective cohort study included all 5539 consecutive patients who underwent mechanical ventilation for at least 3 days from January 1, 2009, to December 31, 2013, at Brigham and Women's Hospital. EXPOSURES Head-of-bed elevation, sedative infusion interruptions, spontaneous breathing trials, thromboprophylaxis, stress ulcer prophylaxis, and oral care with chlorhexidine. MAIN OUTCOMES AND MEASURES Hazard ratios (HRs) for ventilator-associated events, extubation alive vs ventilator mortality, and hospital discharge vs hospital death. Effects were modeled using Cox proportional hazards regression and Fine-Gray competing risk models adjusted for patients' demographic characteristics, comorbidities, unit type, severity of illness, recent procedures, process measure contraindications, day-today markers of clinical status, and calendar year. RESULTS Of 5539 consecutive patients undergoing mechanical ventilation, 3208 were male (57.9%), 2331 female (42.1%), and the mean (SD) age was 61.2 (16.1) years. Sedative infusion interruptions were associated with less time to extubation (HR, 1.81; 95% CI, 1.54-2.12; P < .001) and a lower hazard for ventilator mortality (HR, 0.51, 95% CI, 0.38-0.68; P < .001). Similar associations were found for spontaneous breathing trials (HR for extubation, 2.48; 95% CI 2.23-2.76; P < .001; HR for mortality, 0.28; 95% CI, 0.20-0.38; P = .001). Spontaneous breathing trials were also associated with lower hazards for ventilatorassociated events (HR, 0.55; 95% CI, 0.40-0.76; P < .001). Associations with less time to extubation were found for head-of-bed elevation (HR, 1.38, 95% CI, 1.14-1.68; P = .001) and thromboembolism prophylaxis (HR, 2.57; 95% CI, 1.80-3.66; P < .001) but not ventilator mortality. Oral care with chlorhexidine was associated with an increased risk for ventilator mortality (HR, 1.63; 95% CI, 1.15-2.31; P = .006), and stress ulcer prophylaxis was associated with an increased risk for ventilator-associated pneumonia (HR, 7.69; 95% CI, 1.44-41.10; P = .02). CONCLUSIONS AND RELEVANCE Standard ventilator bundle components vary in their associations with patient-centered outcomes. Head-of-bed elevation, sedative infusion interruptions, spontaneous breathing trials, and thromboembolism prophylaxis appear beneficial, whereas daily oral care with chlorhexidine and stress ulcer prophylaxis may be harmful in some patients.