This study was conducted to better define the pathophysiology, risk factors, and therapeutic approach to exercise-associated hyponatremia. Medical records from all participants in the 1998 Suzuki Rock 'N' Roll Marathon who presented to 14 Emergency Departments (EDs) were retrospectively reviewed to identify risk factors for the development of hyponatremia. Hyponatremic patients were compared to other runners with regard to race time and to other marathon participants seen in the ED with regard to gender, clinical signs of dehydration, and use of nonsteroidal anti-inflammatory drugs (NSAIDs). An original treatment algorithm incorporating the early use of hypertonic saline (HTS) was evaluated prospectively in our own ED for participants in the 1999 marathon to evaluate improvements in sodium correction rate and incidence of complications. A total of 26 patients from the 1998 and 1999 marathons were hyponatremic [serum sodium (SNa) < or =135 mEq/L] including 15 with severe hyponatremia (SNa < or = 125 mEq/L). Three developed seizures and required intubation and admission to an intensive care unit. Hyponatremic patients were more likely to be female, use NSAIDS, and have slower finishing times. Hyponatremic runners reported drinking "as much as possible" during and after the race and were less likely to have clinical signs of dehydration. An inverse relationship between initial SNa and time of presentation was observed, with late presentation predicting lower SNa values. The use of HTS in selected 1999 patients resulted in faster SNa correction times and fewer complications than observed for 1998 patients. It is concluded that the development of exercise-associated hyponatremia is associated with excessive fluid consumption during and after extreme athletic events. Additional risk factors include female gender, slower race times, and NSAID use. The use of HTS in selected patients seems to be safe and efficacious.