STUDY OBJECTIVE Emergency department (ED) -based clinical research has the potential to include patient populations that are typically underrepresented in clinical research. The objective of this study is to assess how emergency clinical care and research processes, informed consent, and patient demographic factors (age, sex, and ethnicity/race) affect enrollment and consent in clinical research in the ED. METHODS This was an analysis of prospectively collected data of all patients (aged 2 to 101 years) eligible for one of 7 clinical research studies from February 2005 to April 2007 in an academic ED. We measured rates of enrollment and consent in the clinical studies. RESULTS One thousand two hundred two of the 4418 patients screened for participation in 7 clinical studies were clinically eligible for enrollment. Of the 868 patients who were able to provide a voluntary decision regarding consent, 639 (73.6%) agreed to participate; an overall enrollment rate of 53.2%. The mean age of patients enrolled was 51.8 years (range 3 to 98 years). Black patients (49.2% enrollment) and Latino patients (18.4% enrollment) were less likely to be enrolled in comparison with white patients (58.3% enrollment) (adjusted odds ratio [OR] of enrollment for blacks=0.64; 95% confidence interval [CI] 0.50 to 0.82; adjusted OR of enrollment for Latinos=0.16; 95% CI 0.08 to 0.33). Enrollment rates were lower among pediatric (40.0%) and geriatric patients (49.1%) in comparison with adult patients ages 18 to 64 years (55.5%) (adjusted OR of enrollment for pediatric patients=0.70, 95% CI 0.34 to 1.43; adjusted OR of enrollment for geriatric patients=0.69, 95% CI 0.53 to 0.90). Unique issues contributing to underenrollment included challenges in consent among pediatric and elderly patients, language issues in Latino patients, reduced voluntary consent rates among black patients, and perhaps underuse of minimal risk waivers. CONCLUSION In a large academic ED, minority, pediatric, and geriatric patients were less likely to be enrolled in acute care clinical research studies than middle-aged whites. Enrollment and consent strategies designed to enhance research participation in these important patient populations may be necessary to address disparities in the development and application of evidence-based emergency and acute care.