BACKGROUND: Enrolling critically ill patients in clinical trials is challenging. We observed that eligible patients at San Francisco General Hospital (SFGH), a public hospital that cares largely for indigent patients, were less likely to be enrolled in a clinical trial of acute lung injury (ALI) than eligible patients at the University of California, San Francisco (UCSF), a university referral center. We examined the reasons for nonenrollment and the impact of the availability of a surrogate decision maker on critical care clinical trials enrollment. METHODS: Data collected from the ARDS Network trial of lower vs traditional tidal volume ventilation for patients with ALI was analyzed. Patient demographics and reasons for nonenrollment were analyzed among 531 consecutively screened patients at the two hospitals: UCSF and SFGH. RESULTS: At UCSF, 1% of screened patients were not enrolled because they lacked surrogates, whereas 18% of screened patients were not enrolled at SFGH because they lacked surrogates. Lack of surrogate was the most common reason for nonenrollment among eligible patients at SFGH. CONCLUSIONS: Critically ill patients with ALI at a public hospital were less likely to be enrolled in a clinical trial than patients at a university hospital primarily because they lacked surrogates. Lack of a surrogate also was a major factor in nonenrollment in other ARDS Network hospitals. In order to provide all affected patients an opportunity to participate in research, innovative strategies for increasing enrollment in critical care research without compromising protection from research risks are needed.