In a 30-month prospective study, we evaluated the efficacy of chlorine dioxide to control Legionella organisms in a water distribution system of a hospital with 364 patient beds and 74 skilled nursing beds. The number of hot water specimens positive for Legionella organisms decreased from 12 (60%) of 20 to 2 (10%) of 20. An extended time (18 months) was needed to achieve a significant reduction in the rate of Legionella positivity among hot water specimens. At the time of writing, no cases of hospital-acquired Legionnaires disease have been detected at the hospital since the chlorine dioxide system was installed in January 2003. Use of chlorine dioxide was safe, based on Environmental Protection Agency limits regarding maximum concentrations of chlorine dioxide and chlorite.