Background Hispanics, particularly those with limited English proficiency, are underrepresented in psychiatric clinical research studies. We developed a bilingual and bicultural research clinic dedicated to the recruitment and treatment of Spanish‐speaking subjects in the Predictors of Remission in Depression to Individual and Combined Treatments (PReDICT) study, a large clinical trial of treatment‐naïve subjects with major depressive disorder (MDD). Methods Demographic and clinical data derived from screening evaluations of the first 1,174 subjects presenting for participation were compared between the Spanish‐speaking site (N = 275) and the primary English‐speaking site (N = 899). Reasons for ineligibility (N = 888) for the PReDICT study were tallied for each site. Results Compared to English speakers, Spanish speakers had a lower level of education and were more likely to be female, uninsured, and have uncontrolled medical conditions. Clinically, Spanish speakers demonstrated greater depression severity, with higher mean symptom severity scores, and a greater number of previous suicide attempts. Among the subjects who were not randomized into the PReDICT study, Spanish‐speaking subjects were more likely to have an uncontrolled medical condition or refuse participation, whereas English‐speaking subjects were more likely to have bipolar disorder or a non‐MDD depressive disorder. Conclusion Recruitment of Hispanic subjects with MDD is feasible and may enhance efforts at signal detection, given the higher severity of depression among Spanish‐speaking participants presenting for clinical trials. Specific approaches for the recruitment and retention of Spanish‐speaking participants are required.