NIMH guidelines to manage subjects who are suicidal during their participation in clinical trials include a full range of procedures to minimize suicidal risk, yet no reports to date have shown how researchers should best implement these guidelines. The architects of the sequenced treatment alternatives to relieve depression (STAR*D) study operationalized and implemented the NIMH guidelines by developing a comprehensive set of procedures to detect, monitor, and manage suicidal subjects during a large, complex, multisite clinical trial. Because of the large size of the study (anticipated n = 4000), the wide geographic distribution, the large number of treating STAR*D clinicians, the broad array of subjects with psychiatric and medical comorbidities, and the focus on treatment-resistant depression, along with the complexity of multiple treatment steps and randomization points in STAR*D, the risk of suicide, safety monitoring of suicidal subjects presented a unique challenge. This paper describes methods derived from the NIMH guidelines used to manage suicidal risk in STAR*D including the use of an interactive voice response system to alert clinicians, regional center directors, and safety officers.