Although enrolling a sufficient number of participants is a challenge for any multisite clinical trial, recruiting patients who are critically ill and receiving mechanical ventilatory support presents additional challenges because of the severity of the patients’ illness and the impediments to their communication. Recruitment challenges related to the research sites, nursing staff, and research participants faced in the first 2 years of a 4-year multisite clinical trial of a patient-directed music intervention for managing anxiety in the intensive care unit were determined. Strategies to overcome these challenges, and thereby increase enrollment, were devised. Individual strategies, such as timing of screening on a unit, were tailored to each participating site to enhance recruitment for this trial. Other strategies, such as obtaining a waiver for a participant’s signature, were instituted across all participating sites. Through implementation of these various strategies, the mean monthly enrollment of participants increased by 50%. Investigators are advised to plan well in advance of starting recruitment for a clinical trial based in an intensive care unit, anticipate peaks and valleys in recruitment, and be proactive in addressing issues creatively as the issues arise.