BACKGROUND: ICUs are increasingly staffed with nurse practitioners/physician assistants (NPs/PAs), but it is unclear how NPs/PAs influence quality of care. We examined the association between NP/PA staffing and in-hospital mortality for patients in the ICU. METHODS: We used retrospective cohort data from the 2009 to 2010 APACHE (Acute Physiology and Chronic Health Evaluation) clinical information system and an ICU-level survey. We included patients aged ≥ 17 years admitted to one of 29 adult medical and mixed medical/surgical ICUs in 22 US hospitals. Because this survey could not assign NPs/PAs to individual patients, the primary exposure was admission to an ICU where NPs/PAs participated in patient care. The primary outcome was patient-level in-hospital mortality. We used multivariable relative risk regression to examine the effect of NPs/PAs on in-hospital mortality, accounting for differences in case mix, ICU characteristics, and clustering of patients within ICUs. We also examined this relationship in the following subgroups: patients on mechanical ventilation, patients with the highest quartile of Acute Physiology Score (> 55), and ICUs with low-intensity physician staffing and with physician trainees. RESULTS: Twenty-one ICUs (72.4%) reported NP/PA participation in direct patient care. Patients in ICUs with NPs/PAs had lower mean Acute Physiology Scores (42.4 vs 46.7, P < .001) and mechanical ventilation rates (38.8% vs 44.2%, P < .001) than ICUs without NPs/PAs. Unadjusted and risk-adjusted mortality was similar between groups (adjusted relative risk, 1.10; 95% CI, 0.92-1.31). This result was consistent in all examined subgroups. CONCLUSIONS: NPs/PAs appear to be a safe adjunct to the ICU team. The findings support NP/PA management of critically ill patients.