Abstract: Individual intensive care unit (ICU) characteristics including staffing, expertise, continuity, and team structure, have been associated with patient outcomes. Separately, some aspects of care in ICUs have been implemented through treatment protocols. The United States Critical Illness and Injury Trials Group-Critical Illness Outcomes Study (USCIITG-CIOS) was designed to determine whether the extent of protocol use in ICUs is associated with hospital survival in a large number of US ICUs. Here, we describe the study protocol and analysis plan approved by the USCIITG-CIOS steering committee. USCIITG-CIOS is a prospective, observational, ecological, multicentered study of mixed ICUs in the US. The data to be collected include organizational information for the ICU (eg, protocol availability and utilization, multidisciplinary staffing assessment), and patient level information (eg, demographics, acute and chronic medical conditions). The primary outcome is all-cause hospital mortality, with the objective being to determine whether there is an association between protocol number and hospital mortality for ICU patients. USCIITG-CIOS is powered to detect a 3% difference in crude hospital mortality between high-protocol and low-protocol use ICUs, dichotomized according to protocol number at the median. The analysis will utilize multivariable regression approaches to adjust for outcome clustering by ICU, with secondary linear analysis of protocol number and mortality and a variety of a priori planned ancillary studies. We anticipate at least 60 ICUs participating in USCIITG-CIOS to enroll approximately 6000 study subjects. USCIITG-CIOS is a multicenter study examining the effect of ICU protocols on patient outcomes. These results will inform our understanding of the relationship between protocol availability, use, and patient outcomes in the ICU. Given the shortage of intensivists worldwide, the results of USCIITG-CIOS can be used to promote more effective and reproducible ICU care and outcomes.