Studies of the volume of drainage over a 24-hour period that is sufficient to allow for the removal of a neck drain after head and neck surgery have not been reported, and thus the timing of drain removal varies among surgeons and institutions. We conducted a prospective study of 47 patients who had undergone major head and neck surgery to determine the safety and cost-effectiveness of removing a neck drain when the amount of drainage over a 24-hour period fell to 50 ml or less. When the volume reached that point in any given patient, the drain was clamped, and if no fluid collection was observed the following day, the drain was removed. We found that drain removal according to this protocol was successful in 91% of cases, as only 4 patients (9%) developed a seroma following removal. No other complications were observed. In a separate analysis, we retrospectively reviewed the cases of 22 other patients who had undergone surgery at a different institution. Their drains were not removed until the drainage volume fell to 25 ml over 24 hours. It took a median of 1.3 days (range: 1 to 3) for drainage to fall from 50 ml to less than 25 ml over 24 hours. We conclude that drains can be removed safely when the volume falls to 50 ml or less over a 24-hour period. This would result in less morbidity, shorter hospital stays, and significant cost savings.